Aminothiazole derivatives and their use as CRF receptor ligands

ABSTRACT

Substituted 4-phenyl-2-aminothiazole derivatives, processes for preparing the same, and the use thereof as corticotropin releasing factor (CRF) antagonists.

This application is a 371 of PCT/FR00/01995 filed Jul. 11, 2000.

The present invention relates to novel branched aminothiazolederivatives, to a process for preparing them and to pharmaceuticalcompositions containing them. These novel thiazole derivatives haveantagonist activity towards CRF (corticotropin releasing factor) and canthus constitute active principles for pharmaceutical compositions.

Corticotropin releasing factor (CRF) is a peptide whose sequence of 41amino acids was characterized by W. Vale et al. in 1981 (Science, 1981,213, 1394-1397). CRF is the main endogenous factor involved inregulating the hypothalamo-hypophysoadrenal axis (release ofadrenocorticotropic hormone: ACTH) and its pathologies, as well as inthe depressive syndromes arising therefrom. CRF also brings about thesecretion of β-endorphin, β-lipotropin and corticosterone. CRF is thusthe physiological regulator of the secretion of adrenocorticotropichormone (ACTH) and more generally of peptides derived frompropiomelanocortin (POMC). Besides its location in the hypothalamus, CRFis also widely distributed in the central nervous system, as well as inextra-neuronal tissues such as the adrenal glands and the testicles. Thepresence of CRF has also been demonstrated in the course of inflammatoryprocesses.

Numerous animal experiments have shown that the central administrationof CRF causes various anxiogenic effects such as modification of thebehaviour in general: for example neophobia, reduction in sexualreceptivity, decrease in food consumption and in slow-wave sleep inrats. The intracerebroventricular injection of CRF also increases theexcitation of the noradrenergic neurons of the locus coeruleus which isoften associated in animals with a state of anxiety. In rats, thecentral or peripheral administration of CRF or of similar peptides (forexample urocortine or sauvagine) induces, in addition to central effectssuch as heightening consciousness and emotional reactivity towards theenvironment, modifications in gastric drainage, in acid secretion, inintestinal transit and in faecal excretion, as well as tension effects.CRF is also involved in the complex regulation of inflammatoryresponses, firstly with a pro-inflammatory role in certain animalmodels, and secondly as an inhibitor of the effects induced byincreasing the vascular permeability following inflammation.

The use of a peptide antagonist, alpha-helical CRF(9-41) (α-CRF) or ofspecific antibodies (Rivier J. et al., Science, 1984, 224, 889-891)confirms the role of this peptide in all of these effects. Theseexperiments also confirmed the important role of CRF in man in theintegration of the complex responses observed during a physiological,psychological or immunological stress both in neuroendocrinal andvisceral as well as behavioural terms (Morley J. E. et al., EndocrineReview, 1987, 8, 3, 256-287; Smith M. A. et al., Horm. Res., 1989, 31,66-71). In addition, clinical data argue in favour of the effectiveinvolvement of CRF in the many disorders resulting from a condition ofstress (Gulley L. R. et al., J. Clin. Psychiatry, 1993, 54, 1, (suppl.),16-19), for example:

the existence of the CRF test (i.v. administration) in man has made itpossible to demonstrate the modification of the ACTH response indepressive patients (Breier A. et al., Am. J. Psychiatry, 1987, 144,1419-1425),

the discovery of a hypersecretion of endogenous CRF in certainpathologies, for example an elevated level of CRF in thecephalorrachidian fluid in non-medicated patients who are depressed orsuffering from a dementia such as Alzheimer's disease (Nemeroff C. B. etal., Science, 1984, 226, 4680, 1342-1343; Regul. Pept., 1989, 25,123-130), or a decreased density of CRF receptors in the cortex ofsuicide victims (Nemeroff C. B. et al., Arch. Gen. Psychiatry, 1988, 45,577-579),

the dysfunctioning of CRF-dependent neurons is even suggested in severepathologies such as Alzheimer's disease, Parkinson's disease,Huntington's chorea and amyotrophic lateral sclerosis (De Souza E. B.,Hospital Practice, 1988, 23, 59).

The central administration of CRF in many animal species producesbehavioural effects similar to those obtained in man under stressconditions. When they are repeated over time, these effects may resultin various pathologies such as: fatigue, hypertension, cardiac andtension disorders, modification of gastric drainage or of faecalexcretion (colitis, irritable bowel), modification of acid secretion,hyperglycaemia, retarded growth, anorexia, neophobia, migraines,reproductive disorders, immunosuppression (inflammatory processes,multiple infections and cancers) and various neuropsychiatric disorders(depression, anorexia nervosa and anxiety).

The intracerebroventricular injection of the reference peptideantagonist, α-CRF, prevents the effects obtained either byadministration of exogenous CRF or by the use of stress-inducing agents(ether, restraint, noise, electric shock, ethanol withdrawal symptoms orsurgery) which are capable by themselves of inducing an increase in thelevel of endogenous CRF. These results are confirmed by the study ofmany antagonist peptide molecules that are structurally similar to CRFand that have a prolonged duration of action relative to α-CRF (RivierJ. et al., J. Med. Chem., 1993, 36, 2851-2859; Menzaghi F. et al., J.Pharmacol. Exp. Ther., 1994, 269, 2, 564-572; Hernandez J. F. et al., J.Med. Chem., 1993, 36, 2860-2867).

Such CRF-antagonist peptide compounds are described, for example, inU.S. Pat. Nos. 5,109,111, 5,132,111 and 5,245,009 and in patentapplications WO 92/22576 and WO 96/19499.

In addition, preliminary studies have shown that tricyclicantidepressants can modulate the level of CRF as well as the number ofCRF receptors in the brain (Grigoriadis D. E. et al.,Neuropsychopharmacology, 1989, 2, 53-60). Similarly, benzodiazepineanxiolytic agents are capable of reversing the effect of CRF (Britton K.T. et al., Psychopharmacology, 1988, 94, 306), although the mechanism ofaction of these substances has not been entirely elucidated. Theseresults reinforce, if necessary, the growing need for non-peptideantagonist molecules for CRF receptors.

It is also important to point out three possible consequences ofconditions of chronic stress, namely immunodepression, fertilitydisorders and the development of diabetes.

CRF exerts such effects by interacting with specific membrane receptorswhich have been characterized in the pituitary gland and the brain ofmany species (mice, rats and man) as well as in the heart, the skeletalmuscle (rats and mice) and in the myometrium and the placenta duringpregnancy.

A large number of 2-aminothiazole derivatives are already known. Patentapplication EP 462 264 describes 2-aminothiazole derivatives, in whichthe tertiary amine in position 2 comprises two substituents eachcontaining at least one hetero atom including an amine derivative. Thesecompounds are platelet activation factor antagonists (PAF-acether) andfind their applications in the treatment of asthma, certain allergic orinflammatory conditions, cardiovascular diseases, hypertension andvarious renal pathologies, or alternatively as contraceptive agents.

Patent application GB 2 022 285 describes compounds with regulatoryactivity on the immune response and with anti-inflammatory properties.These are thiazole derivatives substituted in position 2 with secondaryamine groups.

Certain 2-acylaminothiazole derivatives have been described in patentapplication EP 432 040. These compounds are antagonists ofcholecystokinin and gastrin.

2-Amino-4,5-diphenylthiazole derivatives with anti-inflammatoryproperties are also known (patent application JP-01 75 475).

2-Amino-4-(4-hydroxyphenyl)thiazole derivatives which are useful assynthetic intermediates for the preparation of2,2-diarylchromenothiazole derivatives are also known (patentapplication EP 205 069).

2-(N-Methyl-N-benzylamino)thiazole derivatives are also described in J.Chem. Soc. Perkin, Trans. 1, 1984, 2, 147-153 and in J. Chem. Soc.Perkin, Trans. 1, 1983, 2, 341-347.

Patent application WO 94/01423 describes 2-aminothiazole derivatives.These compounds are used as insecticides; they carry no substitution inposition 5 of the heterocycle.

Similarly, patent application WO 96/16650 describes compounds derivedfrom 2-aminothiazole. These compounds are used as antibiotics.

Patent application EP 283 390 describes, among other thiazolederivatives, 2-(N-alkyl-N-pyridylalkylamino)thiazole derivatives inwhich the amine in position 2 is substituted with an unbranchedpyridylalkyl radical.

These compounds in particular have stimulatory activity on centralcholinergic transmission. They can thus be used as muscarine receptoragonists and find their applications in the treatment of memorydisorders and senile dementias.

2-Aminothiazole derivatives in which the mine in position 2 is atertiary amine bearing a ranched alkyl or aralkyl substituent have beendescribed in EP 576 350 and in EP 659 747 as having affinity for the CRFreceptors. None of these compounds carries a substituted phenyl as asubstituent of the tertiary amine in position 2 of the thiazole nucleus.

U.S. Pat. No. 5,063,245 describes CRF antagonists which allow the invitro displacement of the binding of CRF to its specific receptors at aconcentration in the region of one micromole. Numerous patentapplications regarding non-peptide molecules have since been published,for example patent applications WO 94/13643, WO 94/13644, WO 94/13661,WO 94/13676, WO 94/13677, WO 94/10333, WO 95/00640, WO 95/10506, WO95/13372, WO 95/33727, WO 95/33750, WO 95/34563, EP 691 128 or EP 729758.

It has now been found according to the present invention that certainbranched aminothiazole derivatives, which are the subject of the presentinvention, have excellent affinity towards CRF receptors. Furthermore,given their structure, these molecules have good dispersibility and/orsolubility in solvents or solutions commonly used therapeutically whichgives them pharmacological activity, and also allow the easy preparationof oral and parenteral pharmaceutical forms.

This is surprising and unexpected, since the compounds of the inventionare more active in vivo than compounds of similar structure, inparticular by a more significant inhibition of the response induced byCRF in the hypothalamo-hypophyso-adrenal axis.

One subject of the present invention is compounds, in racemic form or inthe form of a pure enantiomer, of formula:

in which

R₁ and R₂, which may be identical or different, each independentlyrepresent a halogen atom; a hydroxy (C₁-C₅)alkyl; a (C₁-C₅)alkyl; anaralkyl in which the aryl portion is (C₆-C₈) and the alkyl portion is(C₁-C₄); a (C₁-C₅)alkoxy; a trifluoromethyl group; a nitro group; anitrile group; a group —SR in which R represents hydrogen, a(C₁-C₅)alkyl or an aralkyl in which the aryl portion is (C₆-C₈) and thealkyl portion is (C₁-C₄); a group —S—CO—R in which R represents a(C₁-C₅)alkyl or an aralkyl radical in which the aryl portion is (C₆-C₈)and the alkyl portion is (C₁-C₄); a group —COORa in which Ra representshydrogen or a (C₁-C₅)alkyl; a group —CONRaRb with Ra and Rb as definedabove for Ra; a group —NRaRb with Ra and Rb as defined above for Ra; agroup —CONRcRd or —NRcRd in which Rc and Rd constitute, with thenitrogen atom to which they are attached, a 5- to 7-memberedheterocycle; or a group —NHCO—NRaRb with Ra and Rb as defined above forRa;

R₃ represents hydrogen or is as defined above for R₁ and R₂;

or alternatively R₂ constitutes with R₃, when the latter substitutes thephenyl in position 5, a group —X—CH₂—X— in which X independentlyrepresents a CH₂ or an oxygen or sulphur atom;

R₄ represents hydrogen, a (C₁-C₅)alkyl; a hydroxymethyl group; a formylgroup; a halogen atom; or a (C₃-C₅)cycloalkyl group;

R₅ represents an alkenyl of 3 to 6 carbon atoms; an alkynyl of 3 to 6carbon atoms; a cyano(C₁-C₆)alkyl; a (C₁-C₄)alkoxy;

R₆ represents a (C₁-C₆)alkyl; a (C₁-C₆)alkoxy(C₁-C₃)alkyl; a(C₃-C₅)cycloalkyl; a (C₃-C₆)cycloalkyl(C₁-C₆)alkyl; a(C₁-C₆)alkylthio(C₁-C₃)alkyl; a (C₁-C₆)alkylsulphoxy(C₁-C₃)alkyl; a(C₁-C₆)alkylsulphodioxy(C₁-C₃)alkyl;

R₇ represents a phenyl which is unsubstituted, mono-, di- ortrisubstituted in position 3, 4 or 5 with a halogen, with a(C₁-C₅)alkyl, with an —O—CH₂—O— group on two neighbouring carbon atomsof the phenyl, with a —CF₃, —NO₂ or —CN, with a group —COOR₈ or —CONR₈R₉or with a group —CH₂OR₈ in which R₈ and R₉ represent a (C₁-C₃)alkyl,OR₁₀ in which R₁₀ represents a (C₁-C₅)alkyl; or alternatively R₇represents a pyridyl, thiophene, pyrazolyl, imidazolyl,(C₃-C₅)cycloalkyl or (C₃-C₆)cycloalkyl(C₁-C₆)alkyl group;

the addition salts thereof, the hydrates thereof and/or the solvatesthereof.

In the present description, the alkyl groups and the alkoxy groups arelinear or branched.

The term “halogen atom” means a fluorine, chlorine, bromine or iodineatom.

The heterocycles defined for R₇ can optionally be substituted with thesame substituents as those on the phenyl.

According to another of its aspects, the invention relates to compounds,in racemic form or in the form of a pure enantiomer, of formula (I) inwhich:

R₁ and R₂, which may be identical or different, each independentlyrepresent a halogen atom; a (C₁-C₅)alkyl; a (C₁-C₅)alkoxy;

R₃ represents hydrogen or is as defined above for R₁ and R₂;

R₄ represents a (C₁-C₅)alkyl group;

R₅ represents an alkenyl of 3 to 6 carbon atoms; an alkynyl of 3 to 6carbon atoms;

R₆ represents a (C₁-C₆)alkyl; a (C₁-C₆)alkoxy(C₁-C₃)alkyl; a(C₃-C₅)cycloalkyl; a (C₃-C₆)cycloalkyl(C₁-C₆)alkyl;

R₇ represents a phenyl which is unsubstituted or mono- or disubstitutedin position 3 or 4 with a halogen, a (C₁-C₅)alkyl group, a group —CH₂OR₈in which R₈ represents a (C₁-C₃)alkyl or with an —O—CH₂—O— group inposition 3, 4; or alternatively R₇ represents a (C₃-C₅)cycloalkyl group;

the addition salts thereof, the hydrates thereof and/or the solvatesthereof.

According to another of its aspects, a subject of the invention iscompounds, in racemic form or in the form of a pure enantiomer, offormula:

and in which R₁, R₂, R₃, R₅, R₆ and R₇ are as defined for (I), as wellas the addition salts thereof, the hydrates thereof and/or the solvatesthereof.

Among these compounds, the ones more particularly preferred arecompounds, in racemic form or in the form of a pure enantiomer, offormula (I.2)

in which R₁, R₂, R₃, R₆ and R₇ are as defined for (I), as well as theaddition salts thereof, the hydrates thereof and/or the solvatesthereof.

The invention also relates to the compounds of formulae (I), (I.1) and(I.2), in racemic form or in the form of a pure enantiomer, in which R₃is in position 5 of the phenyl, as well as the addition salts thereof,the hydrates thereof and/or the solvates thereof.

According to another of its aspects, the invention relates to compoundschosen from:

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1R)-(1-(3-fluoro-4-methylphenyl)-2-methoxyethyl)]prop-2-ynylaminehydrochloride (Example 31)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-phenylbutyl)]prop-2-ynylaminehydrochloride (Example 33)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-phenylethyl)]prop-2-ynylaminehydrochloride (Example 34)

[4-(2-chloro-4-methoxyphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-phenylethyl)]prop-2-ynylaminehydrochloride (Example 35)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-fluorophenyl)ethyl)]prop-2-ynylaminehydrochloride (Example 36)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-phenylpentyl)]prop-2-ynylaminehydrochloride (Example 37)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1R)-(2-methoxy-1-(4-methoxymethylphenyl)ethyl)]prop-2-ynylaminehydrochloride (Example 40)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(4-methoxymethylphenyl)pentyl)]prop-2-ynylaminehydrochloride (Example 42)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(4-fluorophenyl)pentyl)]prop-2-ynylaminehydrochloride (Example 45)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(cyclopropylphenylmethyl)]prop-2-ynylaminehydrochloride (Example 47)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(3-fluoro-4-methylphenyl)pentyl)]prop-2-ynylaminehydrochloride (Example 49)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylaminehydrochloride (Example 50)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(4-fluorophenyl)butyl)]prop-2-ynylaminehydrochloride (Example 51)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(3-fluoro-4-methoxymethylphenyl)butyl)]prop-2-ynylaminehydrochloride (Example 52)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-chlorophenyl)ethyl)]prop-2-ynylaminehydrochloride (Example 53)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-methylphenyl)ethyl)]prop-2-ynylaminehydrochloride (Example 36)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclobutyl-1-(4-fluorophenyl)ethyl)]prop-2-ynylaminehydrochloride (Example 55)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-bromophenyl)ethyl)]prop-2-ynylaminehydrochloride (Example 56)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3,4-methylenedioxyphenyl)ethyl)]prop-2-ynylaminehydrochloride (Example 57)

[4-(2-chloro-4-methoxyphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylaminehydrochloride (Example 58)

[4-(2,4-dimethoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylaminehydrochloride (Example 59)

[4-(4-methoxy-2,5-dimethylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylaminehydrochloride (Example 60)

[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(3,4-methylenedioxyphenyl)butyl)]prop-2-ynylaminehydrochloride (Example 61)

as well as the corresponding bases, the other addition salts and thesolvates and/or hydrates thereof.

The compounds of the invention in free form generally have weakly basicproperties. However, depending on the nature of the substituents, someof them may show acidic properties.

The salts of the compounds of formula (I) with pharmaceuticallyacceptable acids or bases (when this is possible) are the preferredsalts, but those which may allow the compounds of formula (I) to beisolated, in particular to be purified or to obtain pure isomers, alsoform a subject of the invention.

Among the pharmaceutically acceptable acids for the preparation of theaddition salts to the compounds of formula (I), mention may be made ofhydrochloric acid, hydrobromic acid, phosphoric acid, fumaric acid,citric acid, oxalic acid, sulphuric acid, ascorbic acid, tartaric acid,maleic acid, mandelic acid, methanesulphonic acid, lactobionic acid,gluconic acid, glucaric acid, succinic acid, sulphonic acid andhydroxypropanesulphonic acid.

Among the pharmaceutically acceptable bases for the preparation of theaddition salts to the compounds of formula (I), when these compoundshave acidic properties, mention may be made of sodium hydroxide,potassium hydroxide and ammonium hydroxide.

The compounds according to the invention and the intermediates which areuseful for preparing them are prepared according to methods that arewell known to those skilled in the art, in particular according to EP576 350 and EP 659 747.

The reaction scheme below illustrates one preparation process forsynthesizing the compounds (I).

According to another of its aspects, a subject of the present inventionis also a process for preparing compounds of formula (I), characterizedin that an alpha-halo derivative, preferably an alpha-bromo oralpha-chloro derivative, of formula (III)

in which R₁, R₂, R₃ and R₄ are as defined for (I) and Hal represents ahalogen atom, preferably bromine or chlorine, is reacted with a thioureaof formula:

in which R₆ and R₇ are as defined for (I), to give a compound of formula(II)

in which R₁, R₂, R₃, R₄, R₆ and R₇ are as defined for (I), in order thento subject it to an alkylation reaction to give the compound (I).

The alkylation reactions used in the above process are carried out underthe usual conditions known to those skilled in the art, by the action ofa suitable alkylating agent such as, for example, an alkenyl or alkynylhalide in the presence of a base, preferably sodium hydride.

The derivatives of formula (III) can be obtained from the correpondingnon-halogenated ketones of formula

in which R₁, R₂, R₃ and R₄ are as defined for (I), either (i) by theaction of bromine in a suitable organic solvent, such as acetic acid,carbon tetrachloride or diethyl ether, or (ii) by the action ofquaternary ammonium tribromides according to the method described inBull. Chem. Soc. Japan, 1987, 60, 1159-1160 and 2667-2668, or (iii)alternatively by the action of cupric bromide in an organic solvent,such as a mixture of chloroform and ethyl acetate, according to J. Org.Chem. 1964, 29, 3451-3461. As a variant, the compounds of formula (III)can be obtained by the action of 2-bromopropionyl bromide on asubstituted benzene of formula:

in which R₁, R₂ and R₃ are as defined for (I), by a Friedel-Craftsreaction.

The ketones mentioned above are generally known products orcommercially-available products. These compounds can be prepared byFriedel-Crafts reaction, in the presence of a Lewis acid, according tomethods that are well known to those skilled in the art.

The thiourea derivatives (IV) are obtained from protected thioureaderivatives (V)

in which Prot represents a protecting group, for example benzoyl orpivaloyl, R₆ and R₇ being as defined previously for (I), either by abasic treatment, preferably using aqueous ammonia, sodium hydroxide orhydrazine at a temperature ranging from room temperature to the refluxpoint of the reaction mixture, or by means of an acid treatmentpreferably using hydrochloric acid.

The compounds of formula (V) are prepared by reacting, according toknown methods, an isothiocyanate, for example a benzoyl isothiocyanateor a pivaloyl isothiocyanate, with the corresponding amines of formula(VI):

H₂N—CHR₆R₇  (VI)

in which R₆ and R₇ are as defined for (I).

The preparation of the optically active aminothiazoles, i.e. theproducts in the form of pure enantiomers, is carried out starting withoptically active primary amines according to Scheme 2 below by a processwhich is identical to that described above.

The compounds of formula (I) above also comprise those in which one ormore hydrogen or carbon atoms have been replaced with their radioactiveisotope, for example tritium or carbon-14. Such labelled compounds areuseful in research, metabolism or pharmacokinetic studies, oralternatively in biochemical assays as receptor ligands.

The compounds of the present invention have undergone biochemical andpharmacological studies. They show highly advantageous pharmacologicalproperties. The compounds of the invention displace, at concentrationsof less than 10 μm, the binding of CRF or of related iodinated peptides(urotensine, sauvagine), for example ¹²⁵I-tyrosine CRF, to the receptorspresent on brain membranes or on cells in culture, according to themethod described by E. B. De Souza (J. Neurosci., 1987, 7, 1, 88-100).

The antagonist activity of the compounds according to the invention wasdemonstrated by their ability to inhibit certain activities associatedwith CRF. In particular, the compounds of formula (I) are capable ofinhibiting the secretion of adrenocorticotropic hormone (ACTH) inducedby CRF. The study on the secretion of ACTH induced by CRF was carriedout, in vivo on conscious rats, according to a method adapted from C.Rivier et al., Endocrinology, 1982, 110 (1), 272-278.

CRF is a neuropeptide which controls the activity of thehypothalamo-hypophyso-adrenal axis. This factor is responsible forstress-related behavioural and endocrine responses.

Specifically, it has been demonstrated that CRF can modulate behaviourand also certain functions of the autonomic nervous system (G. F. Koob,F. E. Bloom, Fed. Proc., 1985, 44, 259; M. R. Brown, L. A. Fisher, Fed.Proc., 1985, 44, 243). More particularly, CRF induces the secretion ofcorticotropin (ACTH), β-endorphins and other peptides derived frompro-opiomelanocortin (A. Tazi et al., Régul. Peptides, 1987, 18, 37; M.R. Brown et al., Regul. Peptides, 1986, 16, 321; C. L. Williams et al.,Am. J. Physiol., 1987, G 582, 253).

The compounds of the invention may thus be useful in regulating thesecretion of these endogenous substances. They find their applicationsmore especially as active principles of medicinal products for reducingthe response to stress (behaviour, emotional states, gastrointestinaland cardiovascular disorders, disorders of the immune system) and moregenerally in pathologies involving CRF, for example psychiatricdisorders, anxiety, depression, anorexia nervosa, epilepsy, sexualactivity disorders and fertility disorders, Alzheimer's disease or thelike.

The compounds of the invention are very stable and are thus particularlysuitable for forming the active principle of medicinal products.

The invention also extends to pharmaceutical compositions containing, asactive principle, a compound of formula (I) or one of thepharmaceutically acceptable salts thereof, optionally in combinationwith one or more inert and suitable excipients.

In each dosage unit, the active principle of formula (I) is present inamounts that are suited to the daily doses envisaged. Each dosage unitis appropriately adjusted according to the dosage and the type ofadministration envisaged, for example tablets, gel capsules and thelike, sachets, ampoules, syrups and the like, drops, transdermal ortransmucosal patches, such that such a dosage unit contains 0.5 mg to800 mg of active principle, preferably 0.5 mg to 200 mg.

The compounds according to the invention can also be used in combinationwith another active principle which is useful for the desired treatment,such as, for example, anxiolytic agents, antidepressants or anorexigenicagents.

The compounds of formula (I) are relatively non-toxic; their toxicity iscompatible with their use as medicinal products for treating the abovedisorders and diseases.

The compounds of formula (I) can be formulated in pharmaceuticalcompositions for administration to mammals, including man, for thetreatment of the abovementioned diseases.

The pharmaceutical compositions thus obtained are advantageously invarious forms such as, for example, injectable or drinkable solutions,sugar-coated tablets, tablets or gel capsules. The pharmaceuticalcompositions containing, as active principle, at least one compound offormula (I) or one of the salts thereof are useful in particular forpreventively or curatively treating stress-related conditions and moregenerally in the treatment of any pathology involving CRF, such as, forexample: Cushing's disease, neuropsychiatric disorders such asdepression, anxiety, panic, obessive compulsive disorders, mooddisorders, post-traumatic stress, behavioural disorders, aggressiveness,anorexia, bulimia, hyperglycaemia, premature labour, at-risk pregnancy,retarded growth, sleeping disorders, epilepsy, and all types ofdepression; Alzheimer's disease, Parkinson's disease, Huntington'schorea; amyotrophic lateral sclerosis; vascular, cardiac and cerebraldisorders; sexual activity disorders and fertility disorders;immunodepression, immunosuppression, inflammatory processes, multipleinfections, rheumatoid arthritis, osteoarthritis, uveitis, psoriasis anddiabetes; cancers; gastrointestinal functional disorders andinflammations arising therefrom (irritable and inflammatory bowel,diarrhoea); pain-perception disorders, fibromyalgias which may or maynot be associated with sleeping disorders, fatigue or migraine; symptomsassociated with (alcohol) dependency and withdrawal from drugs.

The dosage can vary widely as a function of the age, weight and state ofhealth of the patient, the nature and seriousness of the complaint, aswell as the route of administration. This dosage comprises the dailyadministration of one or more doses of approximately from 0.5 mg to 800mg, preferably approximately from 0.5 mg to 200 mg.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, transdermal,transmucosal, local or rectal administration, the active principle canbe administered in unit forms of administration, as a mixture withconventional pharmaceutical supports, to animals and to human beings.The appropriate unit forms of administration comprise oral-route formssuch as tablets, gel capsules, powders, granules and oral solutions orsuspensions, sublingual and buccal administration forms, subcutaneous,intramuscular, intravenous, intranasal or intraocular administrationforms and rectal administration forms.

When a solid composition is prepared in the form of tablets, the mainactive principle is mixed with a pharmaceutical vehicle such as gelatin,starch, lactose, magnesium stearate, talc, gum arabic or the like. Thetablets can be coated with sucrose or other suitable materials, oralternatively they can be treated such that they have sustained ordelayed activity and such that they continuously release a predeterminedamount of active principle.

A preparation as gel capsules is obtained by mixing the active principlewith a diluent and pouring the mixture obtained into soft or hard gelcapsules.

A preparation in syrup or elixir form can contain the active principletogether with a sweetener, preferably a calorie-free sweetener, methylparaben and propyl paraben as antiseptic agents, as well as a flavourenhancer and a suitable colorant.

The water-dispersible powders or granules can contain the activeprinciple as a mixture with dispersants or wetting agents, or suspendingagents, such as polyvinylpyrrolidone, as well as with sweeteners orflavour enhancers.

For rectal administration, use is made of suppositories which areprepared with binders that melt at the rectal temperature, for examplecocoa butter or polyethylene glycols.

Aqueous suspensions, isotonic saline solutions or sterile, injectablesolutions which contain pharmacologically compatible dispersants and/orwetting agents, for example propylene glycol or butylene glycol, areused for parenteral, intranasal or intraocular administration.

For transmucosal administration, the active principle can be formulatedin the presence of a promoter such as a bile salt, a hydrophilic polymersuch as, for example, hydroxypropylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose,carboxymethylcellulose, dextran, polyvinylpyrrolidone, pectins,starches, gelatin, casein, acrylic acids, acrylic esters and copolymersthereof, vinyl polymers or copolymers, vinyl alcohols, alkoxy polymers,polyethylene oxide polymers, polyethers or a mixture thereof.

The active principle can also be formulated in the form ofmicrocapsules, optionally with one or more supports or additives.

The active principle can also be in the form of a complex with acyclodextrin, for example α-, β- or γ-cyclodextrin,2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

The examples which follow, which are given in a non-limiting manner,illustrate the invention.

The methods for synthesizing the various intermediates for obtaining thecompounds of the invention are described in the preparations. Theseintermediates are all obtained according to methods that are well knownto those skilled in the art.

The melting points were measured according to the Micro-Köfler techniqueand are expressed in degrees Celsius.

The proton nuclear magnetic resonance (¹H NMR) spectra were acquired inCDCl₃ except where otherwise mentioned, at 200 MHz or at 300 MHz. Thechemical shifts are expressed in p.p.m. and the coupling constants areexpressed in Hertz.

The enantiomeric excesses (ee) are evaluated from the chromatogramsobtained either by chiral-phase HPLC chromatography or by supercriticalfluid chiral (SFC) chromatography.

The optical rotations of the optically active products are characterizedby their [α]^(t) ^(o) _(D) (the concentrations c of the solutionsanalysed are expressed in grams per 100 ml).

The abbreviations used below are as follows: s=singlet; m=multiplet;d=doublet; t=triplet; q=quartet.

The compounds of the invention give an elemental analysis in accordancewith the theoretical result.

The compounds of the invention described in Tables 3 and 5 also give NMRspectra that are in accordance with their structure.

Preparation of the α-Bromo Ketones of Formula (III)

2-Bromo-1-(2-chloro-4-methoxy-5-methylphenyl)propan-1-one Compound III.1

A solution of 46 g (280 mmol) of 4-chloro-2-methoxytoluene in 150 ml ofdichloromethane is stirred at 0° C. and 29.4 g (280 mmol) of2-bromopropionyl bromide are added. 39.2 g (294 mmol) of aluminiumtrichloride are added portionwise to the mixture. This mixture isstirred while allowing the temperature to rise gradually to roomtemperature. After stirring for 4 hours, the reaction mixture is pouredslowly onto ice. 50 ml of 1N of hydrochloric acid and 1 liter of waterare added to this stirred mixture, followed by extraction with 1.2liters of tert-butyl methyl ether. The organic phase is washed withwater, with saturated aqueous sodium-hydrogen carbonate solution, withwater and then with saturated sodium chloride solution. It is dried overanhydrous sodium sulphate and then evaporated to dryness. The cruderesidue is purified by chromatography on silica gel (solvent: 50/1cyclohexane/ethyl acetate). 67 g of compound III-1 are obtained.Yield=82%.

¹H NMR: 7.44 (s, Ar, 1H); 6.86 (s, Ar, 1H); 5.41 (q, J=5.35 Hz, CH, 1H);3.90 (s, OCH₃, 3H); 2.23 (s, CH₃, 3H); 1.91 (d, J=5.35 Hz, CH₃, 3H)

The following compounds were synthesized by the same method:

2-Bromo-1-(2-chloro-4-methoxyphenyl)propan-1-one Compound III.2

2-Bromo-1-(2,4-dichloro-5-methylphenyl)propan-1-one, Compound III.3

2-Bromo-1-(2,4-dimethoxy-5-methylphenyl)propan-1-one Compound III.4

2-Bromo-1-(4-methoxy-2,5-dimethylphenyl)propan-1-one Compound III.5

Preparation of the Racemic Amines of Formula (VI)

First Method

a) 2-Amino-2-(4-fluorophenyl)ethanol Compound I.1

60 ml (60 mmol) of a 1M solution of lithium aluminium hydride intetrahydrofuran are stirred at reflux, followed by portionwise additionof 5 g (29 mmol) of 4-fluoro-DL-α-phenylglycine (Fluka). After stirringat reflux for six hours, the reaction mixture is stirred at 0° C.,followed by slow addition of 2.5 ml of water, 2.5 ml of aqueous 15%sodium hydroxide solution and then 7.5 ml of water. The suspensionobtained is filtered through Celite. The filtrate is concentrated andtaken up in 300 ml of dichloromethane. The solution is washed withsaturated sodium chloride solution, dried over anhydrous sodium sulphateand then evaporated to dryness. 3.3 g of an oily yellow product areobtained. Yield=73%.

MS (MH⁺=156)

¹H NMR: 7.23-7.33 (m, Ar, 2H); 6.95-7.07 (m, Ar, 2H); 4.08 (m, CH, 1H);3.45-3.86 (m, CH₂O, 2H); 2.03 (s, NH₂ and OH, 3H).

b) 1-(4-Fluorophenyl)-2-methoxyethylamine Compound VI.1

0.94 g (23 mmol) of potassium hydride, obtained by washing 2.2 g of anoily suspension with pentane, are suspended in 18 ml of tetrahydrofuranand stirred at 10° C. A solution of 3.3 g (21 mmol) of Compound 1.1 in43 ml of tetrahydrofuran is added slowly. After stirring for sixteenhours at room temperature, a solution of 1.3 ml (20.8 mmol) ofiodomethane in 25 ml of tetrahydrofuran is added over one hour 30minutes. The reaction mixture is stirred for three hours at roomtemperature and is then poured into 300 ml of ice-cold water containingsalt. The mixture is extracted with 500 ml of tert-butyl methyl ether.The organic phase is washed with water and then with saturated sodiumchloride solution, dried over anhydrous sodium sulphate and thenevaporated to dryness. 3.2 g of an oily amine are obtained. Yield=88%.

¹H NMR: 7.24-7.38 (m, Ar, 2H); 6.93-7.05 (m, Ar, 2H); 4.16 (m, CH, 1H);3.45 (dd, CH₂, 1H); 3.36 (s, OCH₃, 3H); 3.29 (d, CH₂, 1H); 1.70 (s, NH₂,2H).

2-Methoxy-1-phenylethylamine, Compound VI.2, is obtained in the sameway.

Second Method

a) Synthesis of Substituted Phenyl Ketones. Compounds 3

Procedure A

1-(3-Fluoro-4-methylphenyl)-2-methoxyethan-1-one Compound 3.1

To prepare the magnesium reagent, 14 g (583 mmol, 1 eq.) of magnesiumshavings are left stirring in the presence of crushed glass and underargon overnight. They are covered with 400 ml of diethyl ether, followedby addition of one spatula-tipful of iodine. 110 g (582 mmol) of4-bromo-2-fluorotoluene dissolved in 700 ml of diethyl ether are addedslowly so as to maintain a gentle reflux, and the reaction mixture isthen heated at reflux for three hours. 39 ml of methoxyacetonitrile (610mmol, 1.1 eq.) are added and the mixture is left to react for two hours.Once the reaction is complete, the reaction mixture is poured into 1.5kg of ice, followed by addition of 300 ml of concentrated hydrochloricacid with stirring. This mixture is extracted with diethyl ether, driedover sodium sulphate and evaporated. 77 g of Compound 3.1 are recovered,which product is used directly in the second step without purifying it.

The following compounds are obtained in the same way:

1-(4-Chloro-3-fluorophenyl)-2-methoxyethan-1-one Compound 3.2

1-(4-Chlorophenyl)-2-methoxyethan-1-one Compound 3.3

3-Cyclopropyl)-1-(4-fluorophenyl)propan-1-one Compound 3.4

Procedure B

2-Methoxy-1-(4-methoxymethylphenyl)ethan-1-one Compound 3.5

A solution of 62 g (308 mmol) of 1-bromo-4-methoxymethylphenyl in 600 mlof tetrahydrofuran is stirred at −70° C. and 200 ml (320 mmol) of a 1.6M solution of butyllithium are added slowly. The reaction mixture isstirred for 30 minutes at −70° C., followed by slow addition of asolution of 50 g (380 mmol) of 2-N-dimethoxy-N-methylacetamide. Thereaction mixture is stirred while allowing the temperature to risegradually to room temperature. After stirring for 4 hours, it is cooledto 0° C. and saturated aqueous ammonium chloride solution is addedslowly. The mixture is extracted with ethyl acetate and the organicphase is washed with water and then with saturated sodium chloridesolution, dried over anhydrous sodium sulphate and then evaporated todryness. The residue obtained is purified by chromatography on silicagel (solvent: 9/1 and then 3/1 cyclohexane/ethyl acetate). 32 g ofketone are obtained. Yield =53%

¹H NMR: 7.89 (d, J=8.1 Hz, Ar, 2H); 7.40 (d, J=8.1 Hz, Ar, 2H); 4.66 (s,OCH₂, 2H); 4.48 (s, OCH₂, 2H); 3.47 (s, CH₃, 3H); 3.38 (s, CH₃, 3H)

b) Synthesis of the Oximes, Compounds 4

1-(3-Fluoro-4-methylphenyl)-2-methoxyethan-1-one oxime Compound 4.1

Procedure A

33 g of hydroxylamine hydrochloride (475 mmol, 1.6 eq.) are mixed with30 ml of water and 100 ml of ethanol. 54 g (296 mmol) of Compound 3.1diluted in 30 ml of ethanol are added at 0° C. Once the addition iscomplete, 60 g of pre-crushed sodium hydroxide pellets (1.5 mol, 5 eq.)are added and the temperature is kept below 30° C. The reaction mixtureis left overnight at room temperature and then placed at 0° C. forneutralization with concentrated hydrochloric acid (pH <7). This mixtureis then extracted with ethyl acetate and the organic phase is washedwith water and with saturated sodium chloride solution. The organicphase is dried over sodium sulphate and evaporated. The oil thusobtained is chromatographed on silica gel using a 1/9 (v/v) ethylacetate/cyclohexane mixture as eluent. 26 g of (Z) isomer and 9 g of (E)isomer are obtained, i.e. a yield Y=45% of (Z) and 16% of (E).

Procedure B

47 g of hydroxylamine hydrochloride (676 mmol, 1.6 eq.) are mixed with275 ml of pyridine. 77 g (423 mmol) of Compound 3.1 are added at 0° C.The reaction mixture is left for five hours at room temperature. Oncethe reaction is complete, the pyridine is evaporated off and the residueis then extracted with dichloromethane. The organic phase is washed withwater and then with saturated sodium chloride solution. The organicphase is dried over sodium sulphate and evaporated, and the oil thusobtained is chromatographed on silica gel using a 1/9 (v/v) ethylacetate/cyclohexane mixture as eluent, to give 42.5 g of compound (Z)and 14 g of compound (E), i.e. a yield Y=51% of Z and 17% of E.

¹H NMR of compound Z: 11.59 (N—OH, s, 1H); 7.20-7.40 (Ar, m, 3H); 4.51(—O—CH₂—, s, 2H); 3.18 (OCH₃, s, 3H); 2.20 (CH₃—Ph, s, 3H)

¹H NMR of compound E: 11.30 (N—OH, s, 1H); 7.20-7.50 (Ar, m, 3H); 4.21(—O—CH₂—, s, 2H); 3.17 (OCH₃, s, 3H); 2.22 (CH₃—Ph, s, 3H).

The following products are obtained in the same way by one of the twoprocedures mentioned above:

1-(4-Chloro-3-fluorophenyl)-2-methoxyethan-1-one oxime Compound 4.2

1-(4-Chlorophenyl)-2-methoxyethan-1-one oxime Compound 4.3

1-Phenylbutan-1-one oxime Compound 4.4

1-(4-Methoxymethylphenyl)-2-methoxyethan-1-one oxime Compound 4.5

1-(4-Methoxymethylphenyl)butan-1-one oxime Compound 4.6

Dicyclobutyl ketone oxime Compound 4.7

1-Phenylpentan-1-one oxime Compound 4.8

c) Synthesis of the Amines Compounds VI

1-(3-Fluoro-4-methylphenyl)-2-methoxyethylamine Compound VI.3

A solution of 1 g of Compound 4.1 (5 mmol) dissolved in 15 ml oftetrahydrofuran is added slowly, at 0° C., to 10 ml of a 1M solution oflithium aluminium hydride in tetrahydrofuran (10 mmol, 8 eq.). Thereaction mixture is allowed to warm to room temperature and is then leftto react for two hours and is refluxed for one hour. The reactionmixture is cooled to 0° C. in order to add 10 ml of water. The aqueousphase is extracted with diethyl ether. The combined organic phases areextracted with 2N hydrochloric acid solution. The acidic aqueous phaseobtained is stirred at 0° C. and 35% sodium hydroxide solution is added.The alkaline solution obtained is extracted with dichloromethane. Theorganic phase is washed with saturated sodium chloride solution and thendried over sodium sulphate and evaporated to dryness. After filtrationon silica using a 95/5 (v/v) dichloromethane/methanol mixture as eluent,0.6 g of Compound VI.3 is obtained. Yield=65%.

¹H NMR: 6.90-7.20 (Ar, m, 3H); 4.14 (—CH—N, dd, J=4 and 8.5, 1H); 3.47(—CH₂—O, dd, J=4 and 9, 1H); 3.37 (OCH₃, s, 3H); 3.32 (—CH₂—O, dd, 1H,J=8.5 and 9); 2.24 (CH₃—Ph, d, J=1.8, 3H); 1.68 (—NH₂, s, 2H).

The following compounds are obtained in the same way:

1-(4-Chloro-3-fluorophenyl)-2-methoxyethylamine Compound VI.4

Dicyclobutylmethylamine Compound VI.5

Third Method

a) Synthesis of O-alkyloxime Compounds 6

Procedure A

1-Phenylbutan-1-one O-methyloxime Compound 6.1

18 g (0.45 mol) of 55% sodium hydride in oil are added portionwise, at0° C. and over one hour, to 66 g (0.40 mol) of 1-phenylbutan-1-one oxime(Compound 4.4) in a mixture of 400 ml of dimethylformamide andtetrahydrofuran (1:1). After addition of 31 ml (0.5 mol) of methyliodide, the reaction mixture gradually becomes very thick. Afteraddition of 50 ml of ethanol, and then water, the reaction mixture isextracted with 4×250 ml of ethyl acetate. The organic phase is washedwith saturated sodium chloride solution, dried over sodium sulphate andthen evaporated under vacuum. 75 g of a pale yellow oil are obtained, asa mixture of geometrical isomers (7% (Z) and 93% (E)). Yield=94% (Z+E).

These two isomers can be separated by chromatography on silica, elutingwith a cyclohexane/ethyl acetate mixture.

¹H NMR: 7.56-7.93 (m, Ar, 2H); 7.24-7.40 (m, Ar, 3H), 3.95 [s, OCH₃,(E)]; 3.82 [s, OCH₃, (Z)]; 2.71 [m, CH₂, (E)]; 2.50 [m, CH₂, (Z)];1.41-1.64 (m, CH₂, 2H); 0.84-1.03 (m, CH₃, 3H)

The following alkylated oximes are obtained in the same way:

1-Phenylpentan-1-one O-methyloxime Compound 6.2

1-(4-Chlorophenyl)-2-methoxyethan-1-one O-benzyloxime Compound 6.3

2-Methoxy-1-(4-methoxymethylphenyl)ethan-1-one O-methyloxime Compound6.4

1-(4-Methoxymethylphenyl)butan-1-one O-methyloxime Compound 6.5

Procedure B

Cyclobutyl 4-fluorophenyl ketone O-benzyloxime Compound 6.6

A solution of 15 g (84 mmol) of cyclobutyl 4-fluorophenyl ketone in 80ml of ethanol is stirred at room temperature and 20.2 g (126 mmol) ofO-benzylhydroxylamine hydrochloride are added. 8.4 g (210 mmol) ofsodium hydroxide are then added portionwise to the mixture, which isstirred for 4 hours at room temperature. Water is added to the mixture,followed by extraction with ethyl acetate. The organic phase is washedwith water until neutral, and then with saturated aqueous sodiumchloride solution. It is dried over sodium sulphate and then evaporatedto dryness. 28.4 g of a mixture of isomers (58% E, 42% Z) are obtained.

¹H NMR (DMSO-d₆): 7.15-7.48 (m, Ar, 9H); 5.07 [s, OCH₂, (E)]; 5.01 [s,OCH₂, (Z)]; 3.68-3.82 [m, CH cyclobutyl, (E)]; 3.36-3.52 [m, CHcyclobutyl, (Z)]; 1.58-2.30 (m, CH₂ cyclobutyl, 6H)

The same method is used to obtain the following compound:

3-Cyclopropyl-1-(4-fluorophenyl)propan-1-one O-benzyloxime Compound 6.7

b) Synthesis of the Amines Compounds VI

1-Phenylbutylamine Compound VI.6

A solution of 14.2 g (0.085 mol) of 1-phenylbutan-1-one O-methyloxime(Compound 6.1) in 85 ml of tetrahydrofuran is added dropwise, underargon, to 85 ml of a 1M solution of lithium aluminium hydride intetrahydrofuran. At the end of the addition, the reaction mixture isrefluxed for one hour thirty minutes. After leaving overnight at roomtemperature, 3.5 ml of H₂O are added, followed by 3.5 ml of 15% sodiumhydroxide and then 10.5 ml of H₂O. The precipitate is filtered off andwashed with diethyl ether. The tetrahydrofuran/diethyl ether filtrate iswashed with water and is then extracted three times with 1N hydrochloricacid solution. The acidic aqueous phases are combined and then basifiedat 0° C. with 35% sodium hydroxide. After extractions withdichloromethane, washes with water, drying over sodium sulphate and thenevaporation under vacuum, 9.3 g of an oil are obtained. Yield=73%.

¹H NMR: 7.11-7.36 (m, Ar, 5H); 3.81-3.95 (m, CH, 1H); 1.73 (s, NH₂, 2H);1.60-1.70 (m, CH₂, 2H); 1.15-1.36 (m, CH₂, 2H); 0.95-0.98 (m, CH₃, 3H).

The following amines are obtained in the same way:

1-Phenylpentylamine Compound VI.7

1-(4-Chlorophenyl)-2-methoxyethylamine Compound VI.8

2-Methoxy-1-(4-methoxymethylphenyl)ethylamine Compound VI.9

1-(4-Methoxymethylphenyl)butylamine Compound VI.10

Cyclobutyl-(4-fluorophenyl)methylamine Compound VI.11

3-Cyclopropyl-1-(4-fluorophenyl)propylamine Compound VI.12

Fourth Method

1-(4-Fluorophenyl)pentylamine Compound VI.13

A solution of 1.21 g (10 mmol) of 4-fluorobenzonitrile in 10 ml oftetrahydrofuran is stirred at 0° C. and 10 ml (10 mmol) of a 1M solutionof boran-tetrahydrofuran are added dropwise. The mixture is stirred forone hour thirty minutes at room temperature and then transferred slowlyinto 18.8 ml of a 1.6 ml solution of butyllithium in hexane, which hasbeen precooled to −78° C. with stirring. The reaction mixture is stirredfor two hours at −78° C. and then hydrolysed at this temperature with 10ml of 2N hydrochloric acid. The organic phase is extracted with 2Nhydrochloric acid and the acidic aqueous phase obtained is neutralizedat 0° C. by slow addition of 35% sodium hydroxide and then extractedwith ethyl acetate. The organic phase is washed with water and then withsaturated sodium chloride solution, dried over anhydrous sodium sulphateand then evaporated to dryness. 0.95 g of an oily amine is obtained.

Yield=53%.

¹H NMR: 7.21-7.31 (m, Ar, 2H); 6.93-7.05 (m, Ar, 2H); 4.13 (t, CH, 1H);1.59-1.75 (m, CH₂, 2H); 1.49 (s, NH₂, 2H); 1.24-1.33 (m, CH₂—CH₂, 4H);0.85 (t, CH₃, 3H).

The following compound is obtained in the same way:

1-(3-Fluoro-4-methylphenyl)pentylamine Compound VI.14

Fifth Method

1-(4-Fluorophenyl)butylamine Compound VI.15

One crystal of iodine is added to a suspension of 2.4 g (100 mmol) ofmagnesium in 30 ml of diethyl ether, followed by 17.4 g (100 mmol) of4-bromofluorobenzene (diluted in 70 ml of diethyl ether) so as to createa gentle reflux. The reaction mixture is refluxed for one hour and thencooled to room temperature and 5.75 g (85 mmol) of butyronitrile dilutedin 30 ml of diethyl ether are added. The reaction mixture is refluxedfor two hours and then cooled and filtered through glass wool. Thefiltrate is stirred at room temperature and 100 ml (100 mmol) of a 1Msolution of lithium aluminium hydride in tetrahydrofuran are addedslowly. The reaction mixture is refluxed for eighteen hours and thencooled to 0° C., followed by successive addition of 3.8 ml of water, 3.8ml of 15% sodium hydroxide and then 11.4 ml of water. The mixture isfiltered through Celite and the filtrate is evaporated to dryness. Theresidue obtained is filtered through silica, eluting with 98/2 (v/v)dichloromethane/methanol. 6.3 g of an oily product are obtained.Yield=37%.

¹H NMR: 7.22-7.36 (m, Ar, 2H); 6.92-7.05 (m, Ar, 2H); 3.87 (t, CH, 1H);1.45-1.65 (m, CH₂, 2H); 1.12-1.40 (m, CH₂, 2H); 0.88 (t, CH₃, 3H)

Preparation of the Racemic Thioureas Compounds IV

N[1-(4-Fluorophenyl)-2-methoxyethyl]thiourea Compound IV.1

6.5 ml (56.6 mmol) of benzoyl chloride are added, at 0° C., to a stirredsolution of 4.5 g (58 mmol) of ammonium isothiocyanate in 115 ml ofacetone. After thirty minutes, 8.6 g (56 mmol) of Compound VI.1dissolved in 100 ml of acetone are added slowly. The reaction mixture isstirred for two hours at room temperature and then concentrated underreduced pressure. The suspension is taken up in 200 ml of tert-butylmethyl ether and 200 ml of water. The organic phase is washed with waterand then with saturated sodium chloride solution, dried over anhydroussodium sulphate and then evaporated to dryness. The evaporation residueis dissolved in 180 ml of ethanol and 5.85 ml (116 mmol) of hydrazinemonohydrate are added to the solution obtained. After stirring forsixteen hours at room temperature, since the reaction is incomplete, afurther 1.7 ml of hydrazine are added. After stirring for 24 hours atroom temperature, the reaction mixture is evaporated. The evaporationresidue is dissolved in 500 ml of ethyl acetate and the organic phase iswashed with water and then with saturated sodium chloride solution,dried over anhydrous sodium sulphate and evaporated to dryness. Theevaporation residue is chromatographed on a column of silica, elutingwith 1/1 (v/v) cyclohexane/ethyl acetate. 8.5 g (40 mmol) of white solidproduct are obtained.

Yield=69%. m.p.=154° C.

¹H NMR (DMSO-d₆): 8.10 (d, NH, 1H); 7.28-7.32 (m, Ar, 2H); 7.08-7.17 (m,Ar and NH₂, 4H); 5.45 (m, CH, 1H); 3.54-3.62 (m, CH—CH₂, 2H); 3.24 (s,OCH₃, 3H)

The following thioureas described in Table 1 are obtained in the sameway:

TABLE 1 (IV)

COMPOUNDS R₇ R₅ m.p. ° C.; NMR; Mass IV.2 

—CH₂OCH₃ 137 IV.3 

—CH₂OCH₃ 186 IV.4 

—(CH₂)₃CH₃ 138 IV.5 

—(CH₂)₂CH₃ 118 IV.6 

—CH₂OCH₃ MS(MH+)255 ¹H RMN: 7.24-7.52(m, Ar, 4H); 7.0(m, NH, 1H);6.02(s, NH₂, 2H): 4.70(m, CH, 1H); 4.42(s, OCH₂, 2H); 3.60(m, OCH₂, 2H);3.37(s, OCH₃, 3H); 3.34(s, OCH₃, 3H). IV.7 

—(CH₂)₂CH₃ MS(MH+)253 ¹H RMN: 7.22-7.34 (m, Ar, 4H); 6.73(m, NH, 1H);5.64(m, NH₂, 2H); 4.41(s, OCH₂, 2H); 4.40(m, CH, 1H); 3.38(s, OCH₃, 3H);1.68-1.82(m, CH₂, 2H); 1.16-1.40 (m, CH₂, 2H); 0.89(t, J=7Hz, CH₃, 3H).IV.8 

—(CH₂)₃CH₃ 154 IV.9 

—(CH₂)₃CH₃ 145 IV.10

—(CH₂)₂CH₃ 107 IV.11

—CH₂OCH₃ ¹H RMN: 7.23-7.40(m, Ar, 4H); 6.80 (d, NH, 1H); 5.87(s, NH₂,2H); 4.90(m, CH, 1H); 3.62(m, OCH₂, 2H); 3.35(s, OCH₃, 3H). IV.12

144 IV.13

—CH₂OCH₃ 109 IV.14

¹H RMN: 7.19-7.29(m, Ar, 2H); 6.98-7.08((m, Ar, 2H); 6.83(s, NH, 1H);5.75(m, NH₂, 2H); 4.40(m, CH, 1H); 2.50-2.60(m, CH, 1H); 2.09-2.15(m, CHd'un CH₂, 1H); 1.68-1.95(m, CH₂, 5H). IV.15

¹H RMN: 7.19-7.30(m, Ar, 2H); 7.02- 7.11(m, Ar, 2H); 6.50(s, NH, 1H);5.55(s, NH₂, 2H); 4.40-4.60(m, CH, 1H); 1.82-2.00(m, CH₂, 2H); 1.15-1.35(m, CH₂, 2H); 0.55-0.75(m, CH cyclopropyle, 1H); 0.38-0.50(m, CH₂cyclopropyle, 2H); 0.01-0.09(m, CH₂ cyclopropyle, 2H).

Preparation of the NH Thiazoles Compounds II

[4-(2-Chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl]-[1-(4-methoxymethylphenyl)butyl]amineCompound II.1

1.92 g (6 mmol) of2-bromo-1-(2-chloro-4-methoxy-5-methylphenyl)propan-1-one (CompoundIII.1) and 1.5 ml of triethylamine are added to 1.4 g (5.54 mmol) of1-(4-methoxymethylphenyl)butylthiourea (Compound IV.7) in 60 ml ofethanol. The reaction mixture is stirred at 85° C. for three hours andthen concentrated under reduced pressure. The residue is taken up in 100ml of dichloromethane and 50 ml of water. The organic phase is washedwith saturated aqueous sodium chloride solution, dried over sodiumsulphate and then evaporated to dryness under vacuum. The crude extractis purified by chromatography on a column of silica gel, eluting with9/1 (v/v) cyclohexane/ethyl acetate. 2.35 g of aminothiazole areobtained. Yield=96%.

MS(MH⁺)=445

¹H NMR: 7.26-7.36 (m, Ar, 4H); 7.10 (s, Ar, 1H); 6.83 (s, Ar, 1H);5.44-5.47 (m, NH, 1H); 4.43 (s, OCH₂, 2H); 4.17-4.33 (m, CH, 1H); 3.81(s, OCH₃, 3H); 3.39 (s, OCH₃, 3H); 2.14 (s, CH₃, 3H); 2.05 (s, CH₃, 3H);1.63-1.88 (m, CH₂, 2H); 1.23-1.48 (m, CH₂, 2H); 0.90 (t, CH₃, 3H).

The following products described in Table 2 were prepared in the sameway:

TABLE 2 (II)

COMPOUNDS R₁/R₂/R₃ R₆ R₇ m.p. ° C.; NMR; Mass II.2  2-Cl 4-OCH₃ 5-CH₃—CH₂OCH₃

120 II.3  2-Cl 4-OCH₃ H —CH₂OCH₃

¹H RMN: 7.22-7.42(m, Ar, 6H); 6.95(d, Ar, 1H); 6.78-6.82 (m, Ar, 1H);6.08(s, NH, 1H); 4.57-4.61(m, CH, 1H); 3.80(s, OCH₃, 3H); 3.48-3.64(m,OCH₂, 2H); 3.35(s, OCH₃, 3H); 2.06(s, CH₃, 3H). II.4  2-Cl 4-Cl 5-CH₃—CH₂OCH₃

¹H RMN: 7.21-7.44(m, Ar, 7H); 5.91(s, NH, 1H); 4.55-4.59 (m, CH, 1H);3.50-3.67(m, OCH₂, 2H): 3.36(s, OCH₃, 3H); 2.31 (s, CH₃, 3H); 2.04(s,CH₃, 3H). II.5  2-Cl 4-OCH₃ 5-CH₃ —CH₂OCH₃

MS (MH⁺) 403 ¹H RMN: 7.24, 7.45(m, Ar, 5H); 7.10(s, Ar, 1H); 6.82(s, Ar,1H); 5.87(d, NH, 1H); 4.53-4.61(m, CH, 1H); 3.84(s, OCH₃, 3H);3.55-3.68(m, OCH₂, 2H); 3.38(s, OCH₃, 3H); 2.14(s, CH₃, 3H); 2.04(s,CH₃, 3H). II.6  2-Cl 4-Cl H —CH₂OCH₃

MS (MH⁺) 393 ¹H RMN: 7.19-7.44(m, Ar, 8H); 5.88(d, NH, 1H); 4.59(m, CH,1H); 3.50-3.67(m, OCH₂, 2H); 3.36(s, OCH₃, 3H); 2.04(s, CH₃, 3H). II.7 2-Cl 4-OCH₃ 5-CH₃ —CH₂OCH₃

MS (MH⁺) 435 ¹H RMN: 7.06-7.25(m, Ar, 4H); 6.83(s, Ar, 1H); 6.00(m, NH,1H); 4.52-4.55(m, CH, 1H); 3.81(s, OCH₃, 3H); 3.51-3.70(m, OCH₂, 2H);3.35(s, OCH₃, 3H); 2.25(s, CH₃, 3H); 2.15(s, CH₃, 3H); 2.07(s, CH₃, 3H).II.8  2-Cl 4-OCH₃ H —(CH₂)₃CH₃

¹H RMN: 7.22-7.37(m, Ar, 6H); 6.96(d, Ar, 1H); 6.78-6.84(dd, Ar, 1H);5.42-5.45(d, NH, 1H); 4.24-4.34(m, CH, 1H); 3.81(s, OCH₃, 3H); 2.06(s,CH₃, 3H); 1.79-1.84(m, CH₂, 2H); 1.31-1.34 (m, CH₂CH₂, 4H); 0.89(t, CH₃,3H). II.9  2-Cl 4-OCH₃ 5-CH₃ —(CH₂)₃CH₃

¹H RMN: 7.26-7.46(m, Ar, 5H); 7.11(s, Ar, 1H); 6.84(s, Ar, 1H); 5.52(s,NH, 1H); 4.23-4.32(m, CH, 1H); 3.83(s, OCH₃, 3H); 2.15(s, CH₃, 3H);2,07(s, CH₃, 3H); 1.80-1.85(m, CH₂, 2H); 1.31-1.42(m, CH₂CH₂, 4H);0.89(t, CH₃, 3H). II.10 2-Cl 4-OCH₃ 5-CH₃ —(CH₂)₂CH₃

¹H RMN: 7.24-7.37(m, Ar, 5H); 7.09(s, Ar, 1H); 6.84(s, Ar, 1H); 5.60(s,NH, 1H); 4.20-4.30(m, CH, 1H); 3.82(s, OCH₃, 3H); 2.14(s, CH₃, 3H);2.05(s, CH₃, 3H); 1.74-2.00(m, CH₂, 2H); 1.24-1.48(m, CH₂, 2H); 0.91(t,CH₃, 3H). II.11 2-Cl 4-OCH₃ H —(CH₂)₂CH₃

¹H RMN: 7.21-7.39(m, Ar, 6H): 6.94(d, Ar, 1H); 6.77-6.83(dd, Ar, 1H);5.84(s, NH, 1H); 4.26-4.29(m, CH, 1H); 3.79(s, OCH₃, 3H); 2.05(s, CH₃,3H); 1.61-1.90(m, CH₂, 2H); 1.20-1.44(m, CH₂, 2H); 0.90(t, CH₃, 3H).II.12 2-Cl 4-OCH₃ 5-CH₃ —CH₂OCH₃

¹H RMN 7.25-7.39(m, Ar, 4H); 7.08(s, Ar, 1H); 6.83(s, Ar, 1H); 5.87(s,NH, 1H); 4.55(m, CH, 1H); 3.81(s, OCH₃, 3H); 3.47-3.65(m, OCH₂, 2H);3.35(s, OCH₃, 3H); 2.14(s, CH₃, 3H); 2.06(s, CH₃, 3H). II.13 2-Cl 4-OCH₃5-CH₃ —CH₂OCH₃

MS(MH⁺) 447 ¹H RMN: 7.30-7.42(m, Ar, 4H); 7.10(s, Ar, 1H); 6.83(s, Ar,1H); 5.90(m, NH, 1H); 4.57(m, CH, 1H): 4.44(s, OCH₂, 2H); 3.81(s, OCH₃,3H); 3.56-3.65(m, OCH₂, 2H); 3.40(s, OCH₃, 3H); 3.35(s, OCH₃, 3H);2.14(s, CH₃, 3H); 2.05(s, CH₃, 3H). II.14 2-Cl 4-Cl 5-CH₃ —CH₂OCH₃

MS(MH⁺) 551 ¹H RMN: 7.22-7.33(m, Ar, 6H); 5.90(d, NH, 1H); 4.55-4.62(m,CH, 1H); 4.46(s, OCH₂, 2H); 3.49-3.71(m, OCH₂, 2H); 3.41(s, OCH₃, 3H);3.36(s, OCH₃, 3H); 3.32(s, CH₃, 3H): 2.06(s, CH₃, 3H). II.15 2-Cl 4-OCH₃H —(CH₂)₂CH₃

MS(MH⁺) 431 ¹H RMN: 7.22, 7.32(m, Ar, 5H); 6.96(d, Ar, 1H); 6.81(d, Ar,1H) 5.51(m, NH, 1H); 4.44(s, OCH₂, 2H); 4.25-4.35(m, CH, 1H); 3.81(s,OCH₃, 3H); 3.41(s, OCH₃, 3H); 2.06(s, CH₃, 3H); 1.68-1.87(m, CH₂, 2H);1.31-1.42(m, CH₂, 2H); 0.91(t, CH₃, 3H). II.16 2-Cl 4-OCH₃ 5-CH₃—(CH₂)₃CH₃

¹H RMN: 7.30-7.36(m, Ar, 2H); 7.16(d, Ar, 1H); 7.02-7.08(m, Ar, 2H);6.88(s, Ar, 1H); 5.76(d, NH, 1H); 4.28-4.31(m, CH, 1H); 3.86(s, OCH₃,3H); 2.20(s, CH₃, 3H); 2.11(s, CH₃, 3H); 1.72-1.84(m, CH₂, 2H);1.27-1.47(m, 2CH₂, 4H); 0.92(t, CH₃, 3H). II.17 2-Cl 4-OCH₃ 5-CH₃—(CH₂)₃CH₃

¹H RMN: 6.96-7.25(m, Ar, 4H); 6.83(s, Ar, 1H); 5.61(s, NH, 1H); 4.22(m,CH, 1H); 3.80(s, OCH₃, 3H); 2.33(s, CH₃, 3H); 2.18(s, CH₃, 3H); 2.06(s,CH₃, 3H); 1.64-1.79(m, CH₂, 2H); 1.18-1.34(m, CH₂—CH₂, 4H); 0.89(t, CH₃,3H). II.18 2-Cl 4-OCH₃ 5-CH₃ —(CH₂)₂CH₃

¹H RMN: 6.96-7.33(m, Ar, 5H); 6.83(s, Ar, 1H); 5.52(d, NH, 1H);4.22-4.32(m, CH, 1H); 3.81(s, OCH₃, 3H); 2.15(s, CH₃, 3H); 2.06(s, CH₃,3H); 1.59-1.84(m, CH₂, 2H); 1.18-1.46(m, CH₂, 2H); 0.90(t, CH₃, 3H).II.19 2-Cl 4-OCH₃ H —(CH₂)₂CH₃

¹H RMN: 6.77-7.34(m, Ar, 7H); 5.53(d, NH, 1H); 4.23-4.33(m, CH, 1H);3.80(s, OCH₃, 3H); 2.06(s, CH₃, 3H); 1.59-1.88(m, CH₂, 2H); 1.17-1.46(m,CH₂, 2H); 0.90(t, CH₃, 3H). II.20 2-Cl 4-OCH₃ 5-CH₃

¹H RMN: 7.16(s, Ar, 1H); 6.86(s, Ar, 1H); 4.84(d, NH, 1H); 3.83(s, OCH₃,3H); 3.14-3.22(m, CH, 1H); 2.13-2.39(m, CHx2, 2H); 2.17(s, CH₃, 3H);2.13(s, CH₃, 3H); 1.67-1.94(m, CH₂x6, 12H). II.21 2-Cl 4-OCH₃ 5-CH₃

¹H RMN: 7.22-7.33(m, Ar, 2H); 7.10(s, Ar, 1H); 6.93-7.05(m, Ar, 2H);6.81(s, Ar, 1H); 5.62(d, NH, 1H); 4.10-4.16(m, CH, 1H); 3.81 (s, OCH₃,3H); 2.37-2.53(m, CH, 1H); 2.15(s, CH₃, 3H); 2.06(s, CH₃, 3H);1.75-1.93(m, 3 CH₂, 6H). II.22 2-Cl 4-OCH₃ 5-CH₃

¹H RMN: 7.25-7.39(m, Ar, 2H); 7.10(s, Ar, 1H); 6.95-7.08(m, Ar, 2H);6.82(s, Ar, 1H); 6.22(m, NH, 1H); 4.25-4.35(m, CH, 1H); 3.81(s, OCH₃,3H);; 2.15(s, CH₃, 3H); 2.07(s, CH₃, 3H); 1.75-2.00(m, CH₂, 2H);1.15-1.35(m, CH₂, 2H); 0.56-0.75(m, CH cyclopropyle, 1H); # 0.36-0.48(m,CH₂ cyclopropyle, 2H); −0.03-0.05 (m, CH₂ cyclopropyle, 2H).

Preparation of the N-Substituted Thiazoles Compounds I EXAMPLE 1[4-(2-Chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl]-[1-(4-fluorophenyl)-2-methoxyethyl)prop-2-ynylamineCompound I.1

50 mg of 60% sodium hydride in oil are added, with stirring and at 0°C., to 500 mg (1.2 mmol) of Compound II.2 in 6 ml of anhydrousdimethylformamide. The reaction mixture is stirred for twenty minutes at0° C., followed by addition of 0.22 ml (2 mmol) of an 80% solution ofpropargyl bromide in toluene. The reaction mixture is stirred for onehour at 10° C., followed by addition of 0.5 ml of ethanol and then 10 mlof water. The mixture is extracted with twice 50 ml of ethyl acetate.The organic phase is washed with water and then with saturated aqueoussodium chloride solution, dried over anhydrous sodium sulphate and thenevaporated to dryness. The crude residue is chromatographed on a columnof silica gel [eluent: 9/1 (v/v) cyclohexane/ethyl acetate]. 400 mg ofthe pure expected compound are obtained. Yield=73%; hydrochloridehemihydrate: m.p.=94° C.

The following products described in Table 3 were prepared in the sameway:

TABLE 3

EXAMPLES R₁/R₂/R₃ R₆ R₇ Mass; m.p. ° C. (HCl)  2 2-Cl 4-OCH₃ H —CH₂OCH₃

70  3 2-Cl 4-Cl 5-CH₃ —CH₂OCH₃

MS (MH⁺) 445; 74  4 2-Cl 4-OCH₃ 5-CH₃ —CH₂OCH₃

MS (MH⁺) 441; 68  5 2-Cl 4-Cl H —CH₂OCH₃

MS (MH⁺) 431; 80  6 2-Cl 4-OCH₃ 5-CH₃ —CH₂OCH₃

MS (MH⁺) 473; 82  7 2-Cl 4-OCH₃ H —(CH₂)₃CH₃

MS (MH⁺) 439; 71  8 2-Cl 4-OCH₃ 5-CH₃ —(CH₂)₃CH₂

MS (MH⁺) 453; 79  9 2-Cl 4-OCH₃ 5-CH₃ —(CH₂)₂CH₃

MS (MH⁺) 439; 69 10 2-Cl 4-OCH₃ H —(CH₂)₂CH₃

MS (MH⁺) 425; 100 11 2-Cl 4-OCH₃ 5-CH₃ —CH₂OCH₃

MS (MH⁺) 475; 58 12 2-Cl 4-OCH₂ 5-CH₃ —CH₂OCH₃

MS (MH⁺) 485; 71 13 2-Cl 4-Cl 5-CH₃ —CH₂OCH₃

MS (MH⁺) 489; 92 14 2-Cl 4-OCH₃ 5-CH₃ —(CH₂)₂CH₃

MS (MH⁺) 483; 93 15 2-Cl 4-OCH₃ H —(CH₂)₂CH₃

MS (MH⁺) 469; 66 16 2-Cl 4-OCH₃ 5-CH₃ —(CH₂)₃CH₃

MS (MH⁺) 471; 61 17 2-Cl 4-OCH₃ 5-CH₃ —(CH₂)₃CH₃

MS (MH⁺) 485; 69 18 2-Cl 4-OCH₃ 5-CH₃ —(CH₂)₂CH₃

MS (MH⁺) 457; 85 19 2-Cl 4-OCH₃ H —(CH₂)₂CH₃

MS (MH⁺) 443; 83 20 2-Cl 4-OCH₃ 5-CH₃

MS (MH⁺) 429; 83 21 2-Cl 4-OCH₃ 5-CH₃

MS (MH⁺) 469; 106 22 2-Cl 4-OCH₃ 5-CH₃

MS (MH⁺) 483; 78

EXAMPLE 23Allyl-[4-(2-chloro-4-methoxyphenyl)-5-methylthiazol-2-yl]-(2-methoxy-1-phenylethyl)amine

A solution of 1.95 g (5 mmol) of aminothiazole (Compound II.3) in 25 mlof dimethylformamide is stirred at 020 C. and 320 mg (8 mmol) of sodiumhydride (at 60% in oil) are added. After stirring for 20 minutes at 0 C., 0.86 ml (10 mmol) of allyl bromide is added. The reaction mixture isstirred at room temperature for one hour, followed by successiveaddition of 2 ml of ethanol and 50 ml of water. The mixture is extractedwith 200 ml of ethyl acetate and the organic phase is washed with waterand then with saturated sodium chloride solution, dried over anhydroussodium sulphate and then evaporated to dryness. The crude residueobtained is chromatographed on a column of silica gel, eluting with 9/1(v/v) cyclohexane/ethyl acetate. 1.25 g (2.7 mmol) of pure product areobtained. Yield=54%; MS (MH⁺) 429; hydrochloride monohydrate; m.p.=70°C.

EXAMPLE 24But-2-ynyl-[4-(2-chloro-4-methoxyphenyl)-5-methylthiazol-2-yl]-[2-methoxy-1-phenylethyl]amine

A solution of 2.8 g (7.17 mmol) of aminothiazole (Compound II.3) in 35ml of dimethylformamide is stirred at 0° C. and 400 mg (10 mmol) ofsodium hydride (at 60% in oil) are added. After stirring for twentyminutes at 0° C., 1.33 g (10 mmol) of 2-bromobutyne (Ferchan) are added.The reaction mixture is stirred at room temperature for one hour,followed by successive addition of 2 ml of ethanol and 50 ml of water.The mixture is extracted with 200 ml of ethyl acetate; the organic phaseis washed with water and then with saturated sodium chloride solution,dried over anhydrous sodium sulphate and then evaporated to dryness. Theresidue obtained is purified by chromatography on a column of silicagel, eluting with 15/1 (v/v) cyclohexane/ethyl acetate. 2.34 g of pureproduct are obtained. Yield=74%; MS (MH+)441; hydrochloride hemihydrate;m.p.=70° C.

Preparation of the Amines in the Form of an Enantiomer Compound VI′

First Method

a) (R)-2-Amino-2-(4-fluorophenyl)ethanol Compound 1′.1

240 ml (240 mmol) of a 1M solution of lithium aluminium hydride intetrahydrofuran are stirred at reflux, followed by portionwise additionof 20 g (118 mmol) of (R)-(4-fluorophenyl)glycine. After stirring atreflux for six hours thirty minutes, the reaction mixture is stirred at0° C., followed by slow addition of 9.5 ml of water, 9.5 ml of 15%sodium hydroxide solution and then 28.5 ml of water. The suspensionobtained is filtered through Celite. The filtrate is concentrated andtaken up in 1 litre of dichloromethane. The solution is washed withsaturated sodium chloride solution, dried over anhydrous sodium sulphateand then evaporated to dryness. A crystallization from isopropyl ethergives 13.22 g (85.2 mmol) of crystalline product. Yield=72%, m.p.=95°C.; MS (MH⁺): 156.

¹H NMR (DMSO-d₆): 7.30-7.41 (m, Ar, AH); 7.01-7.13 (m, Ar, 2H); 4.73 (s,OH, 1H); 3.84 (m, CH, 1H); 3.35-3.45 (m, CH₂O, 2H); 1.82 (s, NH₂, 2H).

b) (R)-1-(4-Fluorophenyl)-2-methoxyethylamine Compound VI′.1

3.64 g (91 mmol) of potassium hydride, obtained by washing 8.1 g of anoily suspension with pentane, are suspended in 70 ml of tetrahydrofuranand stirred at 10° C. A solution of 13.22 g (85 mmol) of Compound 1′.1in 175 ml of tetrahydrofuran is added slowly. After stirring for sixteenhours at room temperature, a solution of 5.2 ml (83.5 mmol) ofiodomethane in 105 ml of tetrahydrofuran is added over two hours. Thereaction mixture is stirred for three hours at room temperature and isthen poured into 1 litre of ice-cold water containing salt. The mixtureis extracted with 1 litre of tert-butyl methyl ether. The organic phaseis washed with water and then with saturated sodium chloride solution,dried over anhydrous sodium sulphate and then evaporated to dryness.11.87 g (70 mmol) of oily amine are obtained.

Yield=82%.

¹H NMR: 7.24-7.38 (m, Ar, 2H); 6.93-7.05 (m, Ar, 2H); 4.16 (m, CH, 1H);3.45 (dd, CH₂, 1H); 3.36 (s, OCH₃, 3H); 3.29 (d, CH₂, 1H) 1.66 (s, NH₂,2H).

The following compound is obtained in the same way, starting with(R)-phenylglycine:

(R)-2-Methoxy-1-phenylethylamine Compound VI′.2

Second Method

a) (S)-2-Amino-3-methyl-1,1-diphenylbutan-1-ol Compound 2′.1

A solution of 600 ml of 3.0 M phenylmagnesium bromide (1790 mmol) indiethyl ether is stirred at 0° C. and diluted with 300 ml of THF,followed by portionwise addition of 50 g (298 mmol) of L-valine-methylester hydrochloride while keeping the temperature below 10° C. Afterstirring for three hours at room temperature, the reaction mixture ispoured slowly into ice-cold ammonium chloride solution. 500 ml ofdiethyl ether and 500 ml of ethyl acetate are added to the mixture,followed by stirring overnight at room temperature. After separation ofthe phases by settling, the aqueous phase is re-extracted with 1 L ofTBME (tert-butyl methyl ether). The combined organic phases are stirredat 0° C. and are acidified slowly with about 40 ml of 35% hydrochloricacid in water. The hydrochloride precipitate thus formed is filtered offand rinsed with TBME. The mixture is then taken up in 1 L ofdichloromethane and 1 L of water and is basified at 0° C. with about 50ml of 35% caustic soda. After separation of the phases by settling, theaqueous phase is re-extracted with 1 L of dichloromethane. The combinedorganic phases are washed with water and then with brine, dried oversodium sulphate and concentrated. After crystallization from isopropylether, 61 g of Compound 2′.1 are obtained (yield=87%)[α  D]_(D)²⁵ = −127.8  ^(∘)  (CHCl₃  c = 0.639)

¹H NMR: 7.00-7.60 (Ar, m, 10H); 5.24 (—OH, s, 1H); 3.66 (—CH—N, d,J=1.5, 1H); 1.53 (—CH—, hept d, J=1.5 and 7, 1H); 1.16 (—NH₂, s, 2H);0.81 (—CH₃, 2d, J=7, 6H).

The following product is obtained in a similar manner, starting withD-valine methyl ester hydrochloride:

(R)-2-Amino-3-methyl-1,1-diphenylbutan-1-ol Compound 2′.2

These compounds are used as chiral auxiliaries in the enantioselectivereduction of the O-benzyl oximes 6′.

b) Synthesis of the Substituted Phenyl Ketones. Compounds 3′

Procedure A

2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one Compound 3′.1

50 ml of diethyl ether and one crystal of iodine are added to 10.2 g(418 mmol) of magnesium turnings and the mixture is stirred at roomtemperature. A solution of 75.35 g (398 mmol) of 4-bromo-2-fluorotoluenein 370 ml of diethyl ether is added over three hours so as to maintain amoderate reflux. The reaction mixture is then refluxed for one hourthirty minutes, after which it is cooled and filtered through glasswool. The solution obtained is added slowly to a solution of 32.3 g (398mmol) of cyclopropylacetonitrile in 230 ml of diethyl ether stirred at0° C. The reaction mixture is stirred overnight at room temperature. Itis then stirred at 0° C. and 200 ml of 2N hydrochloric acid are addedslowly. After separation of the ether phase, the acidic aqueous phase isextracted with ethyl acetate. The combined organic phases are washedwith water and then with saturated sodium chloride solution, dried overanhydrous sodium sulphate and then evaporated to dryness. The crudeextract is purified by chromatography on silica gel (elution solvent:20/1 cyclohexane/ethyl acetate). 53.3 g of ketone 3′-1 are obtained(yield=70%).

¹H NMR: 7.54-7.64 (m, 2H, Ar); 7.22-7.30 (m, 1H, Ar); 2.82 (d, J=6.7 Hz,2H, CH₂); 2.31 (s, 3H, CH₃); 1.07-1.20 (m, 1H, CH cyclopropyl);0.55-0.65 (m, 2H, CH₂ cyclopropyl); 0.15-0.21 (m, 2H, CH₂ cyclopropyl).

The following ketones were synthesized by the same process:

1-(4-Ethylphenyl)-2-methoxyethan-1-one Compound 3′.2

2-Cyclopropyl-1-(4-methylphenyl)ethan-1-one Compound 3′.3

2-Cyclobutyl-1-(4-fluorophenyl)ethan-1-one Compound 3′.4

Procedure B

Method described for Compound 3.5 (reaction of a phenyllithium reagentwith a Weinreb amide):

2-Methoxy-1-(3,4-methylenedioxyphenyl)ethan-1-one Compound 3′.5

1-(4-Methoxymethylphenyl)pentan-1-one Compound 3′.6

1-(3-Fluoro-4-methylphenyl)butan-1-one Compound 3′.7

1-(3-Fluoro-4-methylphenyl)pentan-1-one Compound 3′.8

1-(3-Fluoro-4-methoxymethylphenyl)butan-1-one Compound 3′.9

2-Cyclopropyl-1-(3,4-methylenedioxyphenyl)ethan-1-one Compound 3′.10

1-(3,4-Methylenedioxyphenyl)butan-1-one Compound 3′.11

c) Synthesis of the O-benzyl Oximes. Compounds 6′

The O-benzyl oximes are prepared by O-benzylation of the correspondingoximes according to the process which follows (the starting oximes areobtained from ketones by one of the two synthetic methods describedpreviously for Compound 4.1).

1-(3-Fluoro-4-methylphenyl)-2-methoxyethan-1-one O-benzyloxime Z isomerCompound 6′.1

A solution of 42.5 g (217 mmol) of1-(3-fluoro-4-methylphenyl)-2-methoxyethan-1-one oxime Z (Compound 4.1)in 100 ml of dimethylformamide is stirred at 0° C. and 15.6 g (325 mmol,1.5 eq.) of sodium hydride at 50% in oil are added portionwise. Thereaction mixture is stirred for fifteen minutes, followed by slowaddition of a solution containing 30 ml (280 mmol, 1.3 eq.) of benzylbromide in 100 ml of dimethylformamide. The reaction mixture is stirredfor two hours at room temperature, followed by cooling to 0° C. andaddition of 5 ml of ethanol and then 50 ml of water. The resultingmixture is extracted with ethyl acetate. The organic phase is washedwith water and then with saturated sodium chloride solution. It is thendried over sodium sulphate and evaporated to dryness. The oil thusobtained is purified by chromatography on silica gel (eluent: 7/3 (v/v)cyclohexane/dichloromethane). 39 g of Compound 6′.1 (Z) are obtained;yield=63%.

¹H NMR: 7.10-7.50 (Ar, m, 8H); 5.22 (—O—CH₂—Ph, s, 2H); 4.58 (—CH₂—O, s,2H); 3.28 (OCH₃, s, 3H); 2.26 (CH₃—Ph, d, J=1.8, 3H).

The following compounds are prepared in the same way:

1-(4-Chloro-3-fluorophenyl)-2-methoxyethan-1-one O-benzyloxime (Z)Compound 6′.2

1-(4-Chlorophenyl)-2-methoxyethan-1-one O-benzyloxime (Z) Compound 6′.3

2-Methoxy-1-(3,4-methylenedioxyphenyl)ethan-1-one O-benyloxime (Z)Compound 6′.4

1-(4-Ethylphenyl)-2-methoxyethan-1-one O-benzyloxime (Z) Compound 6′.5

2-Methoxy-1-(4-methoxymethylphenyl)ethan-1-one O-benzyloxime (Z)Compound 6′.6

1-Phenylbutan-1-one O-benzyloxime (E) Compound 6′.7

1-(4-Methoxymethylphenyl)butan-1-one O-benzyloxime (E) Compound 6′.8

1-(4-Methoxymethylphenyl)pentan-1-one O-benzyloxime (E) Compound 6′.9

2-Cyclopropyl-1-phenylethan-1-one O-benzyloxime (E) Compound 6′.10

2-Cyclopropyl-1-(4-fluorophenyl)ethan-1-one O-benzyloxime (E) Compound6′.11

1-(4-Fluorophenyl)pentan-1-one O-benzyloxime (E) Compound 6′.12

Cyclopropylphenyl ketone O-benzyloxime Compound 6′.13

1-(3-Fluoro-4-methylphenyl)butan-1-one O-benzyloxime (E) Compound 6′.14

1-(3-Fluoro-4-methylphenyl)pentan-1-one O-benzyloxime (E) Compound 6′.15

2-Cyclopropyl-1-(3-fluoro-4-methylphenyl)ethan-1-one O-benzyloxime (E)Compound 6′.16

1-(4-Fluorophenyl)butan-1-one O-benzyloxime (E) Compound 6′.17

1-(3-Fluoro-4-methoxymethylphenyl)butan-1-one O-benzyloxime (E) Compound6′.18

2-Cyclopropyl-1-(4-chlorophenyl)ethan-1-one O-benzyloxime (E) Compound6′.19

2-Cyclopropyl-1-(4-methylphenyl)ethan-1-one O-benzyloxime (E) Compound6′.20

2-Cyclobutyl-1-(4-fluorophenyl)ethan-1-one O-benzyloxime (E) Compound6′.21

2-Cyclopropyl-1-(4-bromophenyl)ethan-1-one O-benzyloxime (E) Compound6′.22

2-Cyclopropyl-1-(3,4-methylenedioxyphenyl)ethan-1-one O-benzyloxime (E)Compound 6′.23

1-(3,4-Methylenedioxyphenyl)butan-1-one O-benzyloxime (E) Compound 6′.24

d) Synthesis of the Enantiomeric Amines

(R)-1-(3-Fluoro-4-methylphenyl)-2-methoxyethylamine Compound VI′.3

A solution of 86.5 g of Compound 2′.1 (330 mmol) in 600 ml oftetrahydrofuran is stirred at a temperature below 30° C., followed byslow addition of 670 ml of a 1M borane-tetrahydrofuran solution (670mmol). The temperature is allowed to rise to room temperature over twohours. The reaction medium is then stirred at 0° C. and 39 g (132 mmol)of Compound 6′.1 predissolved in 100 ml of tetrahydrofuran are added.After stirring for twenty hours at room temperature, the reactionmixture is cooled to 0° C. and 1 litre of 2N hydrochloric acid is added.This mixture is left stirring for sixteen hours. The mixture is basifiedat 0° C. by addition of 35% sodium hydroxide, followed by extractionwith ethyl acetate. This extract is washed with water and with saturatedaqueous sodium chloride solution, and then dried over sodium sulphateand evaporated to dryness. The residue obtained is chromatographed on acolumn of silica gel (eluent: 95/5 (v/v) dichloromethane/methanol). 17 gof Compound VI′.3 are obtained; yield=79%.

¹H NMR: 6.90-7.20 (m, Ar, 3H); 4.14 (dd, J₁=4 Hz, J₂=8.5 Hz, CHN, 1H);3.47 (dd, J₁=4 Hz, J₂=9 Hz, —CH₂—O, 1H); 3.37 (s, OCH₃, 3H); 3.32 (dd,J₁=8.5 Hz, J₂=9 Hz, —CH₂—O, 1H); 2.24 (d, J=1.8 Hz, CH₃—Ph, 3H); 1.68(s, —NH₂, 2H)

Chiral HPLC: % enantiomers: Yield=99.5% S=0.5% ee=99.0%

General comments: The enantiomeric excesses (ee) are evaluated from thechromatograms (HPLC or chiral SFC) of these amines or of thecorresponding thioureas IV′

The following are obtained in the same way:

(R)-1-(4-chloro-3-fluorophenyl)-2-methoxyethylamine Compound VI′.4ee=98.2%

(R)-1-(4-chlorophenyl)-2-methoxyethylamine Compound VI′.5 ee=98.6%

(R)-2-methoxy-1-(3,4-methylenedioxyphenyl)ethylamine Compound VI′.6ee>99%

(R)-1-(4-ethylphenyl)-2-methoxyethylamine Compound VI′.7 ee>99%

(R)-2-methoxy-1-(4-methoxymethylphenyl)ethylamine Compound VI′.8 ee>99%

(S)-(1-phenyl)butylamine Compound VI′.9 ee=97.1%

(S)-1-(4-methoxymethylphenyl)butylamine Compound VI′.10 ee=97.1%

(S)-1-(4-methoxymethylphenyl)pentylamine Compound VI′.11 ee=96.8%

(S)-2-cyclopropyl-1-phenylethylamine Compound VI′.12 ee=95.8%

(S)-2-cyclopropyl-1-(4-fluorophenyl)ethylamine Compound VI′.13 ee=95.4%

(S)-1-(4-fluorophenyl)pentylamine Compound VI′.14

(S)-cyclopropylphenylmethylamine Compound VI′.15 ee=90%

(S)-1-(3-fluoro-4-methylphenyl)butylamine Compound VI′.16 ee>99%

(S)-1-(3-fluoro-4-methylphenyl)pentylamine Compound VI′.17 ee=97%

(S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethylamine Compound VI′.18ee>99%

(S)-1-(4-fluorophenyl)butylamine Compound VI′.19 ee=98.4%

(S)-1-(₃-fluoro-4-methoxymethylphenyl)butylamine Compound VI′.20ee=90.5%

(S)-2-cyclopropyl-1-(4-chlorophenyl)ethylamine Compound VI′.21 ee>99%

(S)-2-cyclopropyl-1-(4-methylphenyl)ethylamine Compound VI′.22 ee=85.6%

(S)-2-cyclobutyl-1-(₄-fluorophenyl)ethylamine Compound VI′.23 ee=98.5%

(S)-2-cyclopropyl-1-(4-bromophenyl)ethylamine Compound VI′.24 ee=98.3%

(S)-2-cyclopropyl-1-(3,4-methylenedioxyphenyl)ethylamine Compound VI′.25ee=96.7%

(S)-1-(3,4-methylenedioxyphenyl)butylamine Compound VI′.26 ee=84%

Third Method

To improve the enantiomeric excess, the above amines can be treated withorganic acids in the form of pure enantiomers (for exampleN-acetyl-L-leucine) and recrystallization:

(S)-(1-phenyl)butylamine Compound VI′.9

Salification with N-acetyl-L-leucine

A solution of 10.4 g (60 mmol) of N-acetyl-L-leucine in 70 ml ofanhydrous methanol is stirred at 60° C., followed by dropwise additionof a solution of 9.0 g (60 mmol) of (S)-(1-phenyl)butylamine CompoundVI′.9 (ee=97.1%) in 30 ml of anhydrous methanol. At the end of theaddition, the methanolic solution is brought to the boiling point (totaldissolution) and left to stand overnight. After filtration and rinsingwith 20 ml of cold anhydrous methanol, 7.7 g of crystals are recoveredwhich are dissolved in a minimum of water. After basification with 1Nsodium hydroxide and extraction with dichloromethane, the organic phaseis washed with saturated sodium chloride solution, dried over sodiumsulphate and evaporated under vacuum. 3.4 g of amine are obtained in theform of an oil.

¹H NMR: 7.16-7.36 (m, Ar, 5H); 3.87 (m, —CH—N, 1H); 1.57-1.69 (m,—CH—CH₂, 2H); 1.47 (s, NH₂, 2H); 1.15-1.40 (m, —CH₂CH₃, 2H); 0.88 (t,—CH₂CH₃, 3H).

Chiral HPLC: % enantiomers: S=100% Yield=0% ee=100%.[α]_(D)²⁵ = −22.0  ^(∘)  (c = 1.05, CHCl₃)

Preparation of the Thioureas in the Form of an Enantiomer Compound IV′

First Method

N[(R)-1-(4-fluorophenyl)-2-methoxyethyl]thiourea Compound IV′.1

4.23 ml (36.6 mmol) of benzoyl chloride are added, at 0° C., to astirred solution of 2.83 g (37.2 mmol) of ammonium isothiocyanate in 75ml of acetone. After thirty minutes, 6 g (35.5 mmol) of Compound VI′.1dissolved in 75 ml of acetone are added slowly. The reaction mixture isstirred for two hours at room temperature and then concentrated underreduced pressure. The suspension is taken up in 200 ml of tert-butylmethyl ether and 200 ml of water. The organic phase is washed with waterand then with saturated sodium chloride solution, dried over anhydroussodium sulphate and then evaporated to dryness. The evaporation residueis dissolved in 180 ml of ethanol and 3.75 ml (75 mmol) of hydrazinemonohydrate are added to the solution obtained. After stirring fortwenty-four hours at room temperature, the reaction mixture isevaporated. The evaporation residue is dissolved in 200 ml of ethylacetate and the organic phase is washed with water and then withsaturated sodium chloride solution, dried over anhydrous sodium sulphateand evaporated to dryness. The evaporation residue is chromatographed ona column of silica gel, eluting with 1/1 (v/v) cyclohexane/ethylacetate. 5 g (23 mmol) of a solid white product are obtained; yield=63%;m.p.=119° C.

¹H NMR (DMSO-d₆): 8.10 (d, NH, 1H); 7.28-7.32 (m, Ar, 2H); 7.08-7.17 (m,Ar and NH₂, 4H); 5.45 (m, CH—N, 1H); 3.54-3.62 (m, CH—CH₂, 2H); 3.24 (s,OCH₃, 3H). [α]_(D)¹⁹ = +32.0  ^(∘)  (c = 0.87  CH₂Cl₂).

Supercritical chiral chromatography ee=100%

The following products are obtained in the same way:

N-[(R)-2-methoxy-1-phenylethyl]thiourea Compound IV′.2m.p. = 140  ^(∘)  C.[α]_(D)¹⁹ = +4.6  ^(∘)  (c = 1.0  CH₂Cl₂).

N-[(R)-1-(4-chlorophenyl)-2-methoxyethyl]thiourea Compound IV′.3m.p. = 133^(∘)  C.[α]_(D)¹⁹ = +25.7  ^(∘)  (c = 1.0  4  CH₂Cl₂).

N-[(R)-2-methoxy-1-(3,4-methylenedioxyphenyl)ethyl]thiourea CompoundIV′.4m.p. = 160^(∘)  C.[α]_(D)¹⁹ = +19.4  ^(∘)  (c = 0.68  CH₂Cl₂).

N-[(R)-1-(4-ethylphenyl)-2-methoxyethyl]thiourea Compound IV′.5m.p. = 116^(∘)  C.[α]_(D)¹⁹ = +20.0  ^(∘)  (c = 0.93  CH₂Cl₂).

N-[(S)-1-phenylbutyl]thiourea Compound IV′.6m.p. = 140^(∘)  C.[α]_(D)¹⁹ = +48.7  ^(∘)  (c = 0.82  CH₂Cl₂).

N-[(R)-2-methoxy-1-(4-methoxymethylphenyl)ethyl]thiourea Compound IV′.7

¹H NMR: 7.25-7.36 (m, Ar, 4H); 6.85 (m, NH, 1H); 5.93 (m, NH₂, 2H); 4.73(m, CH—N, 1H); 4.43 (s, O—CH₂, 2H); 3.58-3.65 (m, O—CH₂, 2H); 3.38 (s,OCH₃, 3H); 3.35 (s, O—CH₃, 3H)[α]_(D)¹⁹ = +20.5  ^(∘)  (c = 0.95  CH₂Cl₂).

N-[(S)-1-(4-methoxymethylphenyl)pentyl]thiourea Compound IV′.8

¹H NMR: 7.22-7.35 (m, Ar, 4H); 6.71 (m, NH, 1H); 5.63 (m, NH₂, 2H); 4.42(s, O—CH₂, 2H); 4.40 (m, CH, 1H); 3.39 (S, OCH₃, 3H); 1.68-1.79 (m, CH₂,2H); 1.14-1.30 (m, CH₂—CH₂, 4H); 0.81-0.87 (m, CH₃, 3H).[α]_(D)¹⁹ = +49.8  ^(∘)  (c = 1.04  CH₂Cl₂).

N-[(S)-1-(4-methoxymethylphenyl)butyl]thiourea Compound IV′.9

¹H NMR: 7.20-7.40 (m, Ar, 4H); 6.69 (m, NH, 1H); 5.63 (m, NH₂, 2H); 4.41(s, O—CH₂, 2H); 4.40 (m, CH, 1H); 3.39 (s, OCH₃, 3H); 1.59-1.88 (m,CH—CH₂—CH₂, 2H); 1.15-1.44 (m, CH₂—CH₂—CH₃, 2H); 0.85-0.92 (m, CH₂—CH₃,3H). [α]_(D)¹⁹ = +43.9  ^(∘)  (c = 1.17  CH₂Cl₂).

N-[(S)-2-cyclopropyl-1-phenylethyl]thiourea Compound IV′.10m.p. = 80^(∘)  C.[α]_(D)¹⁹ = +55.0  ^(∘)  (c = 0.97  CH₂Cl₂);

ee=95.8%.

N-[(R)-1-(3-fluoro-4-methylphenyl)-2-methoxyethyl]thiourea CompoundIV′.11m.p. = 149^(∘)  C.[α]_(D)²⁰ = +30.3  ^(∘)  (c = 0.97  CH₂Cl₂).

N-[(R)-1-(3-fluoro-4-chlorophenyl)-2-methoxyethyl]thiourea CompoundIV′.12m.p. = 110^(∘)  C.  [α]_(D)²⁰ = +29.1^(∘)  (c = 1.04  CH₂Cl₂).  

N-[(S)-1-(4-fluorophenyl)pentyl]thiourea Compound IV′.13m.p. = 118^(∘)  C.  [α]_(D)²⁰ = −19.2^(∘)  (c = 0.78  methanol)

N-[(S)-cyclopropylphenylmethyl]thiourea Compound IV′.14

¹H NMR: 7.25-7.41 (m, Ar, 5H); 6.92 (m, NH, 1H); 5.58 (m, NH₂, 2H); 3.92(m, CH, 1H) 1.08-1.25 (m, CH, cyclopropyl, 1H); 0.35-0.69 (m, 2CH₂cyclopropyl, 4H).[α]_(D)²⁰ = +33.5^(∘)  (c = 0.48  methanol);  ee = 90%

N-[(S)-1-(₃-fluoro-4-methylphenyl)butyl]thiourea Compound IV′.15m.p. = 129^(∘)  C.  [α]_(D)²⁰ = 44.4^(∘)  (c = 0.81  CH₂Cl₂);

ee=99%.

N-[(S)-1-(₃-fluoro-4-methylphenyl)pentyl]thiourea Compound IV′.16m.p. = 124^(∘)  C.  [α]_(D)²⁰ = +4.6^(∘)  (c = 1.4  CH₂Cl₂);

ee=97%.

N-[(S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]thiourea CompoundIV′.17m.p. = 91^(∘)  C.  [α]_(D)²² = +55.4^(∘)  (cp = 0.9  CH₂Cl₂);

ee=99%.

N-[(S)-1-(4-fluorophenyl)butyl]thiourea Compound IV′.18

¹H NMR: 7.21-7.28 (m, Ar, 2H); 6.99-7.09 (m, Ar, 2H); 6.75 (s, NH, 1H);5.71 (s, NH₂, 2H); 4.35-4.60 (m, CH, 1H); 1.65-1.85 (m, CH₂, 2H);1.18-1.45 (m, CH₂, 2H) 0.86-0.93 (m, CH₃, 3H)[α]_(D)²² = +49^(∘)  (c = 0.95  CH₂Cl₂);  ee = 98.4%.

N-[(S)-2-cyclopropyl-1-(4-chlorophenyl)ethyl]thiourea Compound IV′.19m.p. = 93.7^(∘)  C.  [α]_(D)²³ = +53^(∘)  (c = 0.5  CH₂Cl₂);

ee=99.1%.

N-[(S)-2-cyclobutyl-1-(4-fluorophenyl)ethyl]thiourea Compound IV′.20m.p. = 104^(∘)  C.  [α]_(D)²⁰ = −21^(∘)  (c = 1  methanol);

ee=98.5%.

N-[(S)-2-cyclopropyl-1-(4-bromophenyl)ethyl]thiourea Compound IV′.21m.p. = 130^(∘)  C.  [α]_(D)²⁰ = +57^(∘)  (c = 0.67  CH₂Cl₂);

ee=98.3%.

N-[(S)-2-cyclopropyl-1-(3,4-methylenedioxyphenyl)ethyl]thiourea CompoundXV′.22m.p. = 125^(∘)  C.  [α]_(D)¹⁹ = +63^(∘)  (c = 0.75  CH₂Cl₂);

ee=96.7%.

Second Method

a) Production by Chromatography of Thioureas in Enantiomeric Form(ee>99%) from Thioureas Enriched in One Enantiomer

N-[(S)-2-cyclopropyl-1-phenylethyl]thiourea Compound IV′.10

Starting with a mixture containing the S enantiomer as the majorityproduct (ee 95.8%), and after separation by chromatography on a ChiracelOJ phase eluting with 97/3 isohexane/ethanol, the pure S enantiomer isobtained (ee 100%).m.p. = 84^(∘)  [α]_(D)¹⁹ = +59.3^(∘)  (c = 0.53  CH₂Cl₂).

N-[(S)-2-cyclopropyl-1-(4-fluorophenyl)ethyl]thiourea Compound IV′.23m.p. = 105^(∘)  [α]_(D)²² = +61.0^(∘)  (c = 0.53  CH₂Cl₂);

ee=100%.

N-[(S)-1-(3-fluoro-4-methoxymethylphenyl)butyl]thiourea Compound IV′.24

¹H NMR: 7.39-7.46 (m, Ar, 1H); 6.93-7.07 (m, Ar, 2H and NH, 1H); 5.85(m, NH₂, 2H); 4.45 (s, O—CH₂, 2H); 4.35 (m, CH, 1H); 3.38 (s, OCH₃, 3H);1.59-1.88 (m, CH—CH₂—CH₂, 2H); 1.18-1.40 (m, CH₂—CH₂—CH₃, 2H); 0.85-0.92(m, CH₂—CH₃, 3H).[α]_(D)¹⁹ = +30.5^(∘)  (c = 0.77  CH₂Cl₂);  ee = 100%.

N-[(S)-2-cyclopropyl-1-(4-methylphenyl)ethyl]thiourea Compound IV′.25

¹H NMR: 7.10-7.20 (m, Ar, 4H); 6.93 (m, NH, 1H); 5.75 (m, NH₂, 2H); 4.43(m, CH, 1H); 2.30 (s, CH₃, 3H); 1.62-1.73 (m, CH₂, 2H); 0.40-0.59 (m, CHand CH₂, cyclopropyl, 3H); 0.04-0.13 (m, CH₂ cyclopropyl, 2H).[α]_(D)¹⁹ = +75.5^(∘)  (c = 0.42  CH₂Cl₂);  ee   = 100%.

N-[(S)-1-(3,4-methylenedioxyphenyl)butyl]thiourea Compound IV′.26F = 140^(∘)  C.  [α]_(D)²⁰ = +40.3  (c = 1.18  CH₂Cl₂);  ee = 100%.

b) Production, By Chromatography, of Optically Active Thioureas (ee>99%)from Racemic Thioureas

N-[(S)-1-phenylpentyl]thiourea Compound IV′.27

Starting with racemic N-(1-phenylpentyl)thiourea, and after separationby chromatography on a Chiracel OJ phase eluting with 95/5isohexane/ethanol, the S enantiomer is obtained in an enantiomericpurity of 99.8%.m.p. = 147^(∘)  C.  [α]_(D)¹⁹ = +46.0^(∘)  (c = 1.00  CH₂Cl₂).

Preparation of the NH Aminothiazoles in the Form of an EnantiomersCompound II′

[4-(2-Chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl]-[(1R)-1-(4-fluorophenyl)-2-methoxyethyl]amineCompound II′.1

4.23 g (14.5 mmol) of2-bromo-1-(2′-chloro-4′-methoxy-5′-methylphenyl)propan-1-one (CompoundIII.1) and 4.2 ml (30 mmol) of triethylamine are added to 3.28 g (14.3mmol) of thiourea (Compound IV′1) dissolved in 70 ml of ethanol. Thereaction mixture is stirred at 90° C. for 3 hours and is thenconcentrated under reduced pressure. The residue is taken up in 200 mlof dichloromethane and 100 ml of water. The organic phase is washed withsaturated sodium chloride solution, dried over anhydrous sodium sulphateand evaporated to dryness. The crude extract is purified bychromatography on a column of silica gel, eluting with 4/1 (v/v)cyclohexane/ethyl acetate. 5.27 g (12.5 mmol) of Compound II′.1 areobtained; yield=87%; MS (MH⁺) 421.

¹H NMR: 7.34-7.44 (m, Ar, 2H); 7.0-7.09 (m, Ar, 3H); 6.83 (s, Ar, 1H);5.87 (d, NH, 1H); 4.57 (m, CH, 1H); 3.81 (s, OCH₃, 3H); 3.46-3.62 (m,OCH₂, 2H); 3.35 (s, OCH₃, 3H); 2.14 (s, CH₃, 3H); 2.04 (s, CH₃, 3H).

The following intermediate compounds were obtained in the same way:

TABLE 4

COMPOUND R₁/R₂/R₃ [*] R₆ R₇ Mass; NMR; m.p. ° C.; α₀ II′.2  2-Cl 4-OCH₃5-CH₃ R —CH₂OCH₃

MS(MH⁺) 403; ¹H RMN(DMSO-D₆): 7.89(d, NH, 1H); 7.26- 7.39(m, Ar, 5H);7.04(s, Ar, 1H); 6.98(s, Ar, 1H); 4.8(m, CH, 1H); 3.79(s, OCH₃, 3H);3.45-3.62(m, OCH₂, 2H); 3.24(s, OCH₃, 3H); 2.08(s, CH₃, 3H); 1.98(s,CH₃, 3H). II′.3  2-Cl 4-Cl 5-CH₃ R —CH₂OCH₃

MS(MH⁺) 407; ¹H RMN: 7.25-7.45(m, Ar, 6H); 7.20(s, Ar, 1H); 5.88(d, NH,1H); 4.57(m, CH, 1H); 3.5-3.67(m, OCH₂, 2H); 3.36(s, OCH₃, 3H); 2.31(s,CH₃, 3H); 2.04(s, CH₃, 3H). II′.4  2-Cl 4-OCH₃ 5-CH₃ R —CH₂OCH₃

MS(MH⁺) 437; ¹H RMN: 7.30-7.38(m, Ar, 4H); 7.08(s, Ar, 1H); 6.83(s, Ar,1H); 5.86(d, NH, 1H); 4.57(m, CH, 1H); 3.81(s, OCH₃, 3H); 3.46-3.70(m,OCH₂, 2H); 3.34(s, OCH₃, 3H); 2.14(s, CH₃, 3H); 2.06(s, CH₃, 3H). II′.5 2-Cl 4-OCH₃ H R —CH₂OCH₃

MS(MH⁺) 433; ¹H RMN: 7.22-7.26(d, Ar, 1H, J=8.5Hz); 6.76-6.95(m, Ar,5H); 5.95(s, O—CH₂—O, 2H); 5.83(d, NH, 1H); 4.45(m, CH, 1H); 3.79(s,OCH₃, 3H); 3.45-3.60(m, OCH₂, 2H); 3.35(s, OCH₃, 3H); 2.05(s, CH₃, 3H).# [α]¹⁹ _(D) = −7.5° c = 1.12 CH₂Cl₂ II′.6  2-Cl 4-OCH₃ 5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 447; 70 [α]¹⁹ _(D) = −6.0° (c = 0.8 CH₂Cl₂) II′.7  2-Cl 4-OCH₃5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 431; ¹H RMN: 7.16-7.35(m, Ar, 4H); 7.10(s, Ar, 1H); 6.83(s,Ar, 1H); 5.86(d, NH, 1H); 4.54(m, CH, 1H); 3.81(s, OCH₃, 3H);3.48-3.64(m, OCH₂, 2H); 3.34(s, OCH₃, # 3H); 2.65(q, J=7.6H_(z), CH₂CH₃,2H); 2.14(s, CH₃, 3H); 2.05(s, CH₃, 3H); 1.23(t, J=7.6H_(z) CH₂CH₃, 3H).II′.8  2-Cl 4-OCH₃ 5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 455; ¹H RMN: 7.12-7.40(m, Ar, 3H); 7.08(s, Ar, 1H); 6.83(s,Ar, 1H); 5.85-5.87(m, NH, 1H); 4.57-4.65(m, CH, 1H); 3.81(s, OCH₃, 3H);3.48-3.70(m, OCH₂, 2H); 3.35(s, OCH₃, 3H); 2.15(s, CH₃, 3H); 2.08(s,CH₃, 3H). II′.9  2-Cl 4-OCH₃ 5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 435; ¹H RMN: 7.06-7.20(m, Ar, 4H); 6.83(s, Ar, 1H);5.83-5.85(m, NH, 1H); 4.51-4.58(m, CH, 1H); 3.81(s, OCH₃, 3H);3.48-3.65(m, OCH₂, 2H); 3.35(s, OCH₃, 3H); 2.25(s, CH₃, 3H); 2.15(s,CH₃, 3H); 2.07(s, CH₃, 3H). II′.10 2-Cl 4-OCH₃ H S —(CH₂)₂CH₃

MS(MH⁺) = 386; ¹H RMN: 7.24-7.34(m, Ar, 5H); 7.24(d, J= 8.5H_(z), Ar,1H); 6.94(d, J=2.5H_(z), Ar, 1H); 6.79(dd, J₁=8.5H_(z) J₂=2.5H_(z), Ar,1H); 5.50(d, NH, 1H); 4.29(m, CH, 1H); # 3.79(s, OCH₃, 3H); 2.04(s, CH₃,3H); 1.68-1.88(m, CH₂, 2H); 1.25-1.45(m, CH₂, 2H); 0.90(t, CH₃, 3H).II′.11 2-Cl 4-OCH₃ 5-CH₃ S —(CH₂)₂CH₃

MS(MH⁺) 401; 64 [α]¹⁹ _(D) = −12.0° (c = 0.86 CH₂Cl₂) II′.12 2-Cl 4-OCH₃5-CH₃ S

MS(MH⁺) = 413; ¹H RMN: 7.21-7.38(m, Ar, 5H); 7.11(s, Ar, 1H); 6.82(s,Ar, 1H); 5.77(d, NH, 1H); 4.38(m, CH, 1H); 3.80(s, OCH₃, 3H); 2.14(s,CH₃, 3H); 2.05(s, CH₃, 3H); 1.65- 1.75(m, CH₂, 2H); 0.58-0.70(m, CHcyclopropyl, 1H); 0-0.5(m, 2CH₂ cyclopropyl, 4H). II′.13 2-Cl 4-OCH₃ H S

MS(MH⁺) 399; ¹H RMN: 7.26-7.40(m, Ar, 5H); 7.25(d, J= 8.5H_(z), Ar, 1H);6.96(d, J=2.6H_(z), Ar, 1H); 6.80(dd, J₁=8.5H_(z) J₂=2.6H_(z), Ar, 1H);4.70(m, NH, 1H); 4.42(m, CH, 1H); 3.80(s, OCH₃, 3H); 2.06(s, CH₃, 3H);1.72(m, CH₂, 2H); # 0.62-0.66(m, CH cyclopropyl, 1H); 0.04-0.49(m, 2CH₂cyclopropyl, 4H). II′.14 2-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) 431 F = 71°; [α]²² _(D) = +17.7° (c = 0.585 CH₂Cl₂) II′.15 2-Cl4-OCH₃ 5-CH₃ S —(CH₂)₃CH₃

MS(MH⁺) 415; ¹H RMN: 7.25-7.35(m, Ar, 5H); 7.10(s, Ar, 1H); 6.83(s, Ar,1H); 5.46(d, NH, 1H); 4.26(m, CH, 1H); 3.81(s, OCH₃, 3H); 2.14(s, CH₃,3H); 2.05(s, CH₃, 3H); 1.76- 1.82(m, CHCH₂CH₂, 2H); 1.2-1.41(m,CH₂CH₂CH₃, 4H); # 0.85(d, CH₃, 3H). [α]²³ _(D) = 9.5° (c = 1.0 CH₂Cl₂)II′.16 2-Cl 4-OCH₃ H S —(CH₂)₃CH₃

¹H RMN: 7.27-7.35(m, Ar, 5H); 7.23(d, J=8.5H_(z), Ar, 1H); 6.94(d,J=2.5H_(z), Ar, 1H); 6.79(dd, J₁=8.5H_(z), J₂=2.5H_(z), Ar, 1H); 5.44(d,NH, 1H); 4.28(m, CH, 1H); 3.79(s, OCH₃, 3H); 2.05(s, CH₃, 3H);1.7-1.83(m, CH—CH₂—CH₂, 2H); # 1.2-1.33(m, —CH₂CH₂CH₃, 4H); 0.85(t,CH₂CH₃, 3H). II′.17 2-Cl 4-OCH₃ H R —CH₂OCH₃

MS(MH⁺) = 433; ¹H RMN: 7.40(d, Ar, 2H); 7.32(d, Ar, 2H); 7.23(d, Ar,1H); 6.94(d, Ar, 1H); 6.80(dd, Ar, 1H); 5.85(d, NH, 1H); 4.58(m, CH,1H); 4.40(s, OCH₂, 2H); 3.80(s, OCH₃, 3H); 3.52-3.65(m, OCH₂, 2H);3.39(s, OCH₃, 3H); 3.35(s, OCH₃, 3H); 2.04(s, CH₃, 3H). II′.18 2-Cl4-OCH₃ 5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 447; ¹H RMN: 7.41(d, Ar, 2H); 7.32(d, Ar, 2H); 7.10(s, Ar,1H); 6.83(s, Ar, 1H); 5.89(m, NH, 1H); 4.57(m, CH, 1H); 4.44(s, OCH₂,2H); 3.81(s, OCH₃, 3H); 3.57- 3.65(m, OCH₂, 2H); 3.39(s, OCH₃, 3H);3.35(s, OCH₃, 3H); # 2.15(s, CH₃, 3H); 2.05(s, CH₃, 3H). II′.19 2-Cl4-OCH₃ 5-CH₃ S —(CH₂)₂CH₃

MS(MH⁺) = 445; ¹H RMN 7.26-7.36(m, Ar, 4H); 7.10(s, Ar, 1H); 6.83(s, Ar,1H); 5.47-5.44(m, NH, 1H); 4.43(s, O—CH₂, 2H); 4.33-4.23(m, CH, 1H);3.81(s, OCH₃, 3H); 3.39(s, # OCH₃, 3H); 2.14(s, CH₃, 3H); 2.05(s, CH₃,3H); 1.91-1.62(m, # CH₂, 2H); 1.48-1.21(m, CH₂CH₃, 2H); 0.89(t, CH₃,3H). II′.20 2-Cl 4-OCH₃ 5-CH₃ S —(CH₂)₃CH₃

MS(MH⁺) = 459; ¹H RMN: 7.27-7.35(m, Ar, 4H); 7.10(s, Ar, 1H); 6.83(s,Ar, 1H); 5.43(m, NH, 1H); 4.43(s, OCH₂, 2H); 4.22-4.31(m, CH, 1H);3.81(s, CH₃, 3H); 3.39(s, OCH₃, 3H); # 2.15(s, CH₃, 3H); 2.05(s, CH₃,3H); 1.73-1.82(m, CH₂, 2H); # 1.21-1.36(m, —CH₂—CH₂, 4H); 0.82-0.88(m,CH₃, 3H). II′.21 2-Cl 4-OCH₃ 5-CH₃ S —(CH₂)₃CH₃

MS(MH⁺) = 433; ¹H RMN: 7.25-7.32(m, Ar, 2H); 7.10(s, Ar, 1H);6.95-7.06(m, Ar, 2H); 6.82(s, Ar, 1H); 5.52(d, J=5.7Hz, NH, 1H);4.20-4.30(m, CH, 1H); 3.81(s, OCH₃, 3H); 2.14(s, CH₃, 3H); 2.06(s, CH₃,3H); 1.69-1.82(m, CH₂, 2H); 1.21- # 1.37(m, CH₂CH₂, 4H); 0.85(t, CH₃,3H). II′.22 2-Cl 4-OCH₃ H S

MS(MH⁺) = 385; ¹H RMN: 7.28-7.43(m, Ar, 5H); 7.23(d, J=8.5Hz, Ar, 1H);6.87(d, J=2.5Hz, Ar, 1H); 6.80(dd, J₁=8.5Hz, J₂=2.5Hz, Ar, 1H); 5.32(m,NH, 1H); 3.79(s, OCH₃, 3H); 3.74(m, CH, 1H); 2.03(s, CH₃, 3H);1.15-1.30(m, CH # cyclopropyl, 1H); 0.38-0.67(m, 2CH₂ cyclopropyl, 4H).II′.23 2-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 399; ¹H RMN: 7.26-7.43(m, Ar, 5H); 7.10(s, Ar, 1H); 6.83(s,Ar, 1H); 5.63(m, NH, 1H); 3.81(s, OCH₃, 3H); 3.74(m, CH, 1H); 2.36(s,CH₃, 3H); 2.04(s, CH₃, 3H); 1.15- 1.30(m, CH cyclopropyl, 1H);0.35-0.67(m, 2CH₂ cyclopropyl, 4H). II′.24 2-Cl 4-OCH₃ 5-CH₃ S—(CH₂)₂CH₃

MS(MH⁺) = 433; ¹H RMN (DMSO-D₆); 7.82(d, J=8.2Hz, NH, 1H); 7.10-7.22(m,Ar, 3H); 7.03(s, Ar, 1H); 6.98(s, Ar, 1H); 4.41-4.52(m, CH, 1H); 3.79(s,OCH₃, 3H); 2.17(d, J=1.65Hz, # CH₃, 3H); 2.08(s, CH₃, 3H); 1.97(s, CH₃,3H); 1.57-1.75(m, # CH₂, 2H); 1.23-1.37(m, CH₂, 2H); 0.84(t, CH₃, 3H).II′.25 2-Cl 4-OCH₃ 5-CH₃ S —(CH₂)₃CH₃

MS(MH⁺) = 447; ¹H RMN: 7.10-7.17(m, Ar, 2H); 6.95- 7.02(m, Ar, 2H);6.83(s, Ar, 1H); 5.43(m, NH, 1H); 4.19- 4.26(m, CH, 1H); 3.81(s, OCH₃,3H); 2.25(d, J=1.84Hz, CH₃, 3H); 2.14(s, CH₃, 3H); 2.06(s, CH₃, 3H);1.70-1.85(m, CH₂, # 2H); 1.19-1.35(m, CH₂CH₂, 4H); 0.84(t, CH₃, 3H).II′.26 2-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 445; ¹H RMN: 7.00-7.17(m, Ar, 4H); 6.83(s, Ar, 1H); 5.66(m,NH, 1H); 4.30-4.40(m, CH, 1H); 3.81(s, OCH₃, 3H); 2.25(d, J=1.84Hz, CH₃,3H); 2.14(s, CH₃, 3H); 2.06(s, CH₃, 3H); 1.64-1.71(m, CH₂, 2H);0.54-0.63(m, CH # cyclopropyl, 1H); 0.40-0.52(m, CH₂ cyclopropyl, 2H)0.06- 0.15(m, CH₂ cyclopropyl, 2H). II′.27 2-Cl 4-OCH₃ 5-CH₃ S—(CH₂)₂CH₃

MS(MH⁺) = 419; ¹H RMN 7.25-7.33(m, Ar, 2H); 6.95- 7.09(m, Ar, 3H);6.83(s, Ar, 1H); 5.49(m, NH, 1H); 4.22- 4.32(m, CH, 1H); 3.81(s, OCH₃,3H); 2.14(s, CH₃, 3H); 2.06(s, CH₃, 3H); 1.70-1.85(m, CH₂, 2H);1.18-1.37(m, CH₂, # 2H); 0.90(t, CH₃, 3H). II′.28 2-Cl 4-OCH₃ 5-CH₃ S—(CH₂)₂CH₃

MS(MH⁺) = 463; ¹H RMN: 7.32-7.40(m, Ar, 1H); 7.01- 7.14(m, Ar, 3H);6.83(s, Ar, 1H); 5.41(d, J=5.9Hz, NH, 1H); 4.48(s, OCH₂, 2H);4.24-4.34(m, CH, 1H); 3.81(s, OCH₃, 3H); 3.41(s, OCH₃, 3H); 2.14(s, CH₃,3H); 2.06(s, CH₃, 3H); # 1.65-1.83(m, CH₂, 2H); 1.20-1.42(m, CH₂, 2H);0.90(t, CH₃, 3H). II′.29 2-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 447; ¹H RMN: 7.30(s, Ar, 4H); 7.08(s, Ar, 1H); 6.83(s, Ar,1H); 5.69(m, NH, 1H); 4.35-4.45(m, CH, 1H), 3.81(s, OCH₃, 3H); 2.14(s,CH₃, 3H); 2.06(s, CH₃, 3H); 1.64- 1.72(m, CH₂, 2H); 0.53-0.63(m, CHcyclopropyl, 1H); 0.42- # 0.52(m, CH₂ cyclopropyl, 2H); 0.02-0.15(m, CH₂cyclopropyl, 2H). II′.30 2-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 427; ¹H RMN: 7.25(d, J=8.1Hz, Ar, 2H); 7.13(d, J=8.1Hz, Ar,2H); 7.10(s, Ar, 1H); 6.83(s, Ar, 1H); 5.76(m, NH, 1H); 4.29-4.39(m, CH,1H); 3.81(s, OCH₃, 3H); 2.33(s, CH₃, 3H); 2.14(s, CH₃, 3H); 2.05(s, CH₃,3H); 1.65-1.72(m, # CH₂, 2H); 0.54-0.69(m, CH cyclopropyl, 1H);0.35-0.50(m, CH₂ cyclopropyl, 2H); 0.06-0.15(m, CH₂ cyclopropyl, 2H).II′.31 2-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 445; ¹H RMN: 7.23-7.30(m, Ar, 2H); 6.95- 7.09(m, Ar, 3H);6.81(s, Ar, 1H); 5.57(m, NH, 1H); 4.11- 4.21(m, CH, 1H); 3.81(s, OCH₃,3H); 2.14(s, CH₃, 3H); 2.06(s, CH₃, 3H); 1.50-2.25(m, CH₂, CH and (CH₂)₃cyclobutyl, # 9H). II′.32 2-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 491; ¹H RMN: 7.41-7.48(m, Ar, 2H); 7.20- 7.25(m, Ar, 2H);7.10(s, Ar, 1H); 6.81(s, Ar, 1H); 5.96(m, NH, 1H); 4.29-4.39(m, CH, 1H);3.81(s, OCH₃, 3H); 2.15(s, CH₃, 3H); 2.05(s, CH₃, 3H); 1.56-1.67(m, CH₂,2H); 0.51- # 0.65(m, CH cyclopropyl, 1H); 0.34-0.50(m, CH₂ cyclopropyl,2H); 0.03-0.14(m, CH₂ cyclopropyl, 2H). II′.33 2-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 457; ¹H RMN: 7.10(s, Ar, 1H); 6.74-6.86(m, Ar, 4H); 5.94(s,OCH₂O, 2H); 5.93(s, NH, 1H); 4.24-4.34(m, CH, 1H); 3.81(s, OCH₃, 3H);2.15(s, CH₃, 3H); 2.07(s, CH₃, 3H); 1.64-1.72(m, CH₂, 2H); 0.51-0.63(m,CH cyclopropyl, 1H); # 0.40-0.50(m, CH₂ cyclopropyl, 2H); 0.02-0.13(m,CH₂ cyclopropyl, 2H). II′.34 2-Cl 4-OCH₃ H S

MS(MH⁺) = 431; ¹H RMN: 6.97-7.28(m, Ar, 5H); 6.79- 6.85(m, Ar, 1H);6.16(m, NH, 1H); 4.32-4.42(m, CH, 1H); 3.81(s, OCH₃, 3H); 2.26(d,J=1.85Hz, CH₃, 3H); 2.07(s, CH₃, 3H); 1.69-1.76(m, CH₂, 2H);0.53-0.66(m, CH cyclopropyl, # 1H); 0.40-0.50(m, CH₂ cyclopropyl, 2H)0.04-0.14(m, CH₂ cyclopropyl, 2H). II′.35 2-OCH₃ 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 441; ¹H RMN: 7.00-7.18(m, Ar, 4H); 6.45(s, Ar, 1H); 5.98(m,NH, 1H); 4.28-4.38(m, CH, 1H); 3.85(s, OCH₃, 3H); 3.79(s, OCH₃, 3H);2.26(d, J=1.82Hz, CH₃, 3H); 2.14(s, # CH₃, 3H); 2.07(s, CH₃, 3H);1.66-1.72(m, CH₂, 2H); 0.53- 0.68(m, CH cyclopropyl, 1H); 0.40-0.50(m,CH₂ cyclopropyl, 2H), 0.04-0.14(m, CH₂ cyclopropyl, 2H). II′.36 2-CH₃4-OCH₃ 5-CH₃ S

MS(MH⁺) = 425; ¹H RMN: 6.96-7.17(m, Ar, 4H); 6.64(s, Ar, 1H); 5.83(m,NH, 1H); 4.32-4.42(m, CH, 1H); 3.80(s, OCH₃, 3H); 2.25(d, J=1.85Hz, CH₃,3H); 2.14(s, 2CH₃, 6H); 2.07(s, # CH₃, 3H); 1.63-1.70(m, CH₂, 2H);0.53-0.66(m, CH cyclopropyl, 1H); 0.39-0.50(m, CH₂ cyclopropyl, 2H);0.02- 0.14(m, CH₂ cyclopropyl, 2H). II′.37 2-Cl 4-OCH₃ 5-CH₃ S—(CH₂)₂CH₃

MS(MH⁺) = 445; ¹H RMN: 7.10(s, Ar, 1H); 6.72-6.82(m, Ar, 4H); 5.93(s,OCH₂O, 2H); 5.60(d, NH, 1H); 4.12-4.22(m, CH, 1H); 3.80(s, OCH₃, 3H);2.14(s, CH₃, 3H); 2.06(s, CH₃, 3H); # 1.64-1.85(m, CH₂, 2H);1.22-1.45(m, CH₂, 2H); 0.85-0.89(m, CH₃, 3H).

Preparation of the N-Substituted Aminothiazoles in the Form of anEnantiomer EXAMPLE 25[4-(2-Chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl]-[(1R)-1-(4-fluorophenyl)-2-methoxyethyl]prop-2-ynylamine

A solution of 2.5 g (5.9 mmol) of Compound II′.1 in 30 ml ofdimethylformamide is stirred at 0° C. and 260 mg (6.5 mmol) of sodiumhydride in 60% in oil are added. The reaction mixture is stirred for 20minutes at 0° C., followed by addition of 0.83 ml (7.5 mmol) of an 80%solution of propargyl bromide in toluene. The reaction mixture isstirred for one hour at 10° C., followed by addition, at 0° C., of 2 mlof ethanol and then 50 ml of water. The mixture is extracted with 200 mlof ethyl acetate. The organic phase is washed with water and then withsaturated sodium chloride solution, dried over anhydrous sodium sulphateand then evaporated to dryness. The crude residue is chromatographed ona column of silica gel, eluting with 9/1 (v/v) cyclohexane/ethylacetate. 2.14 g of a gummy pure product are obtained; yield=80%; MS(MH⁺) 459.

¹H NMR: 7.37-7.46 (m, Ar, 2H); 7.14 (s, Ar, 1H); 6.95-7.07 (m, Ar, 2H);6.81 (s, Ar, 1H); 5.54 (m, CH, 1H); 4.15 (dd, J₁=18 Hz, J₂=2.4 Hz,CH₂—N, 1H); 4.00-4.08 (m, OCH₂, 2H); 3.98 (dd, J₁=18 Hz, J₂=2.4 Hz,CH₂—N, 1H); 3.82 (s, OCH₃, 3H); 3.40 (s, OCH₃, 3H); 2.18 (t, J=2.4 Hz,CH propargyl, 1H); 2.17 (s, CH₃, 3H); 2.16 (s, CH₃, 3H).[α]_(D)¹⁹ = −127^(∘)  C.  (c = 0.99  CH₂Cl₂)

Supercritical chiral HPLC: ee=99.4%.

TABLE 5

EXAMPLES R₁/R₂/R₃ [*] R₆ R₇ Mass; m.p. ° C. (HCl); α_(D); ee 26 2-Cl4-OCH₃ 5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 475 81; [α]¹⁹ _(D) = −153.0° (c = 1.00 CH₂Cl₂) ee = 98.4% 272-Cl 4-OCH₃ H R —CH₂OCH₃

MS(MH⁺) = 471 100; [α]¹⁹ _(D) = −132.0° (c = 0.84 CH₂Cl₂) ee = 100% 282-Cl 4-OCH₃ 5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 485 97; [α]¹⁹ _(D) = −161.0° (c = 0.97 CH₂Cl₂) 29 2-Cl 4-OCH₃5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 469 63; [α]²⁰ _(D) = −133.0° (c = 1.05 CH₂Cl₂) 30 2-Cl 4-OCH₃5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 493 75; [α]²⁰ _(D) = −137.5° (c = 1.005 CH₂Cl₂) 31 2-Cl 4-OCH₃5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 473 86; [α]²⁰ _(D) = −130.1° (c = 1.095 CH₂Cl₂) 32 2-Cl 4-OCH₃H S —(CH₂)₂CH₃

MS(MH⁺) = 425 84; [α]²⁰ _(D) = −206.0° (c = 1.00 CH₂Cl₂) ee = 98.9% 332-Cl 4-OCH₃ 5-CH₃ S —(CH₂)₂CH₃

MS(MH⁺) = 439 95; [α]²⁰ _(D) = −175° (c = 0.65 methanol) ee = 99.4% 342-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 451 102; [α]²⁰ _(D) = −231.0° (c = 1.14 CH₂Cl₂) ee = 100% 352-Cl 4-OCH₃ H S

MS(MH⁺) = 437 74; [α]¹⁹ _(D) = −208.0° (c = 1.02 CH₂Cl₂) ee = 100% 362-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 469 94; [α]²² _(D) = −214.0° (c = 0.685 CH₂Cl₂) 37 2-Cl 4-OCH₃5-CH₃ S —(CH₂)₃CH₃

MS(MH⁺) = 453 75; [α]²⁰ _(D) = −207.0° (c = 0.97 CH₂Cl₂) ee = 99.5% 382-Cl 4-OCH₃ H S —(CH₂)₃CH₃

MS(MH⁺) = 439 88; [α]²⁰ _(D) = −174.0° (c = 1.00 CH₂Cl₂) ee = 99.5% 392-Cl 4-OCH₃ H R —CH₂OCH₃

MS(MH⁺) = 471 47; [α]¹⁹ _(D) = −140.4° (c = 0.72 CH₂Cl₂) ee = 97.3% 402-Cl 4-OCH₃ 5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 485 54; [α]²⁰ _(D) = −132.2° (c = 0.93 CH₂Cl₂) ee = 97.3% 412-Cl 4-OCH₃ 5-CH₃ S —(CH₂)₂CH₃

MS(MH⁺) = 483 56; [α]²⁰ _(D) = −178.0° (c = 0.38 CH₂Cl₂) 42 2-Cl 4-OCH₃5-CH₃ S —(CH₂)₃CH₃

MS(MH⁺) = 497 52; [α]²⁰ _(D) = −165.2° (c = 0.97 CH₂Cl₂) 43 2-Cl 4-OCH₃5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 441 76; [α]¹⁹ _(D) = −120.0° (c = 0.92 CH₂Cl₂) ee = 99.7% 442-Cl 4-Cl 5-CH₃ R —CH₂OCH₃

MS(MH⁺) = 445 69; [α]¹⁹ _(D) = −103.0° (c = 0.73 CH₂Cl₂) ee = 99.7% 452-Cl 4-OCH₃ 5-CH₃ S —(CH₂)₃CH₃

MS(MH⁺) = 471 77; [α]¹⁹ _(D) = −213° (c = 1.06 CH₂Cl₂) 46 2-Cl 4-OCH₃ HS

MS(MH⁺) = 423 73; [α]¹⁹ _(D) = −10.5° (c = 0.93 CH₂Cl₂) 47 2-Cl 4-OCH₃5-CH₃ S

MS(MH⁺) = 437 106; [α]¹⁹ _(D) = −106° (c = 1.0 CH₂Cl₂) 48 2-Cl 4-OCH₃5-CH₃ S —(CH₂)₂CH₃

MS(MH⁺) = 471 81; [α]¹⁹ _(D) = −225° (c = 0.85 CH₂Cl₂) ee = 99% 49 2-Cl4-OCH₃ 5-CH₃ S —(CH₂)₃CH₃

MS(MH⁺) = 485 73; [α]²⁰ _(D) = −197° (c = 0.45 CH₂Cl₂) ee = 98.5% 502-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 483 115; [α]²⁰ _(D) = −230° (c = 0.77 CH₂Cl₂) ee = 99.2% 512-Cl 4-OCH₃ 5-CH₃ S —(CH₂)₂CH₃

MS(MH⁺) = 457 84; [α]²⁰ _(D) = −188° (c = 0.98 CH₂Cl₂) ee = 98.4% 522-Cl 4-OCH₃ 5-CH₃ S —(CH₂)₂CH₃

MS(MH⁺) = 501 79; [α]²⁰ _(D) = −160° (c = 0.43 CH₂Cl₂) 53 2-Cl 4-OCH₃5-CH₃ S

MS(MH⁺) = 447 98; [α]²⁰ _(D) = −187° (c = 0.90 CH₂Cl₂) ee = 100% 54 2-Cl4-OCH₃ 5-CH₃ S

MS(MH⁺) = 465 105; [α]²⁰ _(D) = −218° (c = 0.92 CH₂Cl₂) 55 2-Cl 4-OCH₃5-CH₃ S

MS(MH⁺) = 483 89; [α]²⁰ _(D) = −182° (c = 1.05 methanol) ee = 99% 562-Cl 4-OCH₃ 5-CH₃ S

MS(MH⁺) = 530 141; [α]²⁰ _(D) = −298° (c = 0.41 CH₂Cl₂) 57 2-Cl 4-OCH₃5-CH₃ S

MS(MH⁺) = 495 131; [α]¹⁹ _(D) = −219° (c = 0.80 CH₂Cl₂) 58 2-Cl 4-OCH₃ HS

MS(MH⁺) = 469 75; [α]²⁰ _(D) = −216° (c = 0.825 CH₂Cl₂) 59 2-OCH₃ 4-OCH₃5-CH₃ S

MS(MH⁺) = 479 96; [α]²⁰ _(D) = −208° (c = 0.79 CH₂Cl₂) 60 2-CH₃ 4-OCH₃5-CH₃ S

MS(MH⁺) = 463 114; [α]²⁰ _(D) = −205° (c = 0.82 CH₂Cl₂) 61 2-Cl 4-OCH₃5-CH₃ S —(CH₂)₂CH₃

MS(MH⁺) = 483 95; [α]²⁰ _(D) = −230° (c = 1.26 CH₂Cl₂)

What is claimed is:
 1. A compound of formula (I):

in which R₁ and R₂, which may be identical or different, eachindependently represent a halogen atom; a hydroxy (C₁-C₅)alkyl; a(C₁-C₅)alkyl; an aralkyl in which the aryl portion is (C₆-C₈) and thealkyl portion is (C₁-C₄); a (C₁-C₅)alkoxy; a trifluoromethyl group; anitro group; a nitrile group; a group —SR in which R representshydrogen, a (C₁-C₅)alkyl or an aralkyl in which the aryl portion is(C₆-C₈) and the alkyl portion is (C₁-C₄); a group —S—CO—R in which Rrepresents a (C₁-C₅)alkyl or an aralkyl radical in which the arylportion is (C₆-C₈) and the alkyl portion is (C₁-C₄); a group —COORa inwhich Ra represents hydrogen or a (C₁-C₅)alkyl; a group —CONRaRb with Raand Rb as defined above for Ra; a group —NRaRb with Ra and Rb as definedabove for Ra; a group —CONRcRd or —NRcRd in which Rc and Rd constitute,with the nitrogen atom to which they are attached, a 5- to 7-memberedheterocycle; or a group —NHCO—NRaRb with Ra and Rb as defined above forRa; R₃ represents hydrogen or is as defined above for R₁ and R₂; oralternatively R₂ constitutes with R₃, when the latter substitutes thephenyl in position 5, a group —X—CH₂—X— in which X independentlyrepresents a CH₂ or an oxygen or sulphur atom; R₄ represents hydrogen, a(C₁-C₅)alkyl; a hydroxymethyl group; a formyl group; a halogen atom; ora (C₃-C₅)cycloalkyl group; R₅ represents an alkynyl of 3 to 6 carbonatoms; R₆ represents a (C₁-C₆)alkyl; a (C₁-C₆)alkoxy(C₁-C₃)alkyl; a(C₃-C₅)cycloalkyl; a (C₃-C₆)cycloalkyl(C₁-C₆)alkyl; a(C₁-C₆)alkylthio(C₁-C₃)alkyl; a (C₁-C₆)alkylsulphoxy(C₁-C₃)alkyl; or a(C₁-C₆)alkylsulphodioxy(C₁-C₃)alkyl; R₇ represents a phenyl which isunsubstituted, mono-, di- or trisubstituted in position 3, 4 or 5 with ahalogen, with a (C₁-C₅)alkyl, with an —O—CH₂—O— group on twoneighbouring carbon atoms of the phenyl, with a —CF₃, —NO₂ or —CN, witha group —COOR₈ or —CONR₈R₉ or with a group  CH₂OR₈ in which R₈ and R₉represent a (C₁-C₃)alkyl, OR₁₀ in which R₁₀ represents a (C₁-C₅)alkyl;or alternatively R₇ represents a pyridyl, thiophene, pyrazolyl,imidazolyl, (C₃-C₅)cycloalkyl or (C₃-C₆)cycloalkyl(C₁-C₆)alkyl group; orthe acid or base addition salts thereof, the hydrates thereof and/or thesolvates thereof.
 2. A compound according to claim 1 wherein: R₁ and R₂,which may be identical or different, each independently represent ahalogen atom; a (C₁-C₅)alkyl; or a (C₁-C₅)alkoxy; R₃ represents hydrogenor is as defined above for R₁ and R₂; R₄ represents a (C₁-C₅)alkylgroup; R₅ represents an alkynyl of 3 to 6 carbon atoms; R₆ represents a(C₁-C₆)alkyl; a (C₁-C₆)alkoxy(C₁-C₃)alkyl; a (C₃-C₅)cycloalkyl; or a(C₃-C₆)cycloalkyl(C₁-C₆)alkyl; R₇ represents a phenyl which isunsubstituted or mono- or disubstituted in position 3 or 4 with ahalogen, a (C₁-C₅)alkyl group, a group —CH₂OR₈ in which R₈ represents a(C₁-C₃)alkyl or with an —O—CH₂—O— group in position 3, 4; oralternatively R₇ represents a (C₃-C₅)cycloalkyl group.
 3. A compoundaccording to claim 2 of formula (I.1):

in which R₁, R₂, R₃, R₅, R₆ and R₇ are as defined in claim 2, or theacid or base addition salts thereof, the hydrates thereof and/or thesolvates thereof.
 4. A compound according to claim 3 of formula (I.2):

in which R₁, R₂, R₃, R₆ and R₇ are as defined in claim 3, or the acid orbase addition salts thereof, the hydrates thereof and/or the solvatesthereof.
 5. A compound according to claim 4 wherein R₃ is in position 5of the phenyl.
 6. A compound according to claim 1 selected from thegroup consisting of:[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1R)-(1-(3-fluoro-4-methylphenyl)-2-methoxyethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-phenylbutyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-phenylethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxyphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-phenylethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-4-fluorophenyl)ethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-phenylpentyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1R)-(2-methoxy-1-(4-methoxymethylphenyl)ethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(4-methoxymethylphenyl)pentyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(4-fluorophenyl)pentyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(cyclopropylphenylmethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(3-fluoro-4-methylphenyl)pentyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(4-fluorophenyl)butyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(3-fluoro-4-methoxymethylphenyl)butyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-chlorophenyl)ethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-methylphenyl)ethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclobutyl-1-(4-fluorophenyl)ethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(4-bromophenyl)ethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3,4-methylenedioxyphenyl)ethyl)]prop-2-ynylamine;[4-(2-chloro-4-methoxyphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine;[4-(2,4-dimethoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine;[4-(4-methoxy-2,5-dimethylphenyl)-5-methylthiazol-2-yl][(1S)-(2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl)]prop-2-ynylamine;and[4-(2-chloro-4-methoxy-5-methylphenyl)-5-methylthiazol-2-yl][(1S)-(1-(3,4-methylenedioxyphenyl)butyl)]prop-2-ynylamine;or the acid or base addition salts, solvates or hydrates thereof.
 7. Aprocess for preparing a compound according to claim 1 which comprisesreacting a compound of formula (II):

with a compound of the formula R₅X in the presence of a base in whichR₁, R₂, R₃, R₄, R₅, R₆ and R₇ are as defined in claim 1 and X is halide.8. A pharmaceutical composition containing a compound according to claim1 in combination with a pharmaceutically acceptable excipient.
 9. Acompound according to claim 5 in the form of a single enantiomer.
 10. Acompound selected from the group consisting of the hydrochloride saltsof the compounds of claim
 6. 11. A pharmaceutical composition containinga compound according to claim 4 in combination with a pharmaceuticallyacceptable excipient.
 12. A pharmaceutical composition containing acompound according to claim 6 in combination with a pharmaceuticallyacceptable excipient.